297 results on '"Drew, M."'
Search Results
2. Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma
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Anagnostou, Valsamo, Bruhm, Daniel C, Niknafs, Noushin, White, James R, Shao, Xiaoshan M, Sidhom, John William, Stein, Julie, Tsai, Hua-Ling, Wang, Hao, Belcaid, Zineb, Murray, Joseph, Balan, Archana, Ferreira, Leonardo, Ross-Macdonald, Petra, Wind-Rotolo, Megan, Baras, Alexander S, Taube, Janis, Karchin, Rachel, Scharpf, Robert B, Grasso, Catherine, Ribas, Antoni, Pardoll, Drew M, Topalian, Suzanne L, and Velculescu, Victor E
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Vaccine Related ,Immunization ,Human Genome ,Genetics ,Biotechnology ,Clinical Research ,Cancer ,Inflammatory and immune system ,Good Health and Well Being ,B-Lymphocytes ,Gene Expression ,Gene Expression Profiling ,Genomics ,Humans ,Immune Checkpoint Inhibitors ,Immunotherapy ,Melanoma ,Mutation ,Prospective Studies ,T-Lymphocytes ,Transcription ,Genetic ,Transcriptome ,T cell repertoire ,cancer genomics ,immune checkpoint blockade ,integrative predictive model ,melanoma ,multi-omics ,Biomedical and clinical sciences - Abstract
In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.
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- 2020
3. Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma
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Grasso, Catherine S, Tsoi, Jennifer, Onyshchenko, Mykola, Abril-Rodriguez, Gabriel, Ross-Macdonald, Petra, Wind-Rotolo, Megan, Champhekar, Ameya, Medina, Egmidio, Torrejon, Davis Y, Shin, Daniel Sanghoon, Tran, Phuong, Kim, Yeon Joo, Puig-Saus, Cristina, Campbell, Katie, Vega-Crespo, Agustin, Quist, Michael, Martignier, Christophe, Luke, Jason J, Wolchok, Jedd D, Johnson, Douglas B, Chmielowski, Bartosz, Hodi, F Stephen, Bhatia, Shailender, Sharfman, William, Urba, Walter J, Slingluff, Craig L, Diab, Adi, Haanen, John BAG, Algarra, Salvador Martin, Pardoll, Drew M, Anagnostou, Valsamo, Topalian, Suzanne L, Velculescu, Victor E, Speiser, Daniel E, Kalbasi, Anusha, and Ribas, Antoni
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Genetics ,Vaccine Related ,Human Genome ,Immunization ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Cell Line ,Cell Line ,Tumor ,Female ,Gene Expression Profiling ,Humans ,Immune Checkpoint Inhibitors ,Interferon-gamma ,Ipilimumab ,Male ,Melanoma ,Middle Aged ,Nivolumab ,T-Lymphocytes ,Transcriptome ,Young Adult ,RNA-seq ,anti-CTLA-4 ,anti-PD-1 ,biopsies ,clinical trial ,immune checkpoint blockade ,immune exclusion ,interferon-γ ,resistance ,response ,transcriptomics ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
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- 2020
4. Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells
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Chung, Liam, Orberg, Erik Thiele, Geis, Abby L, Chan, June L, Fu, Kai, Shields, Christina E DeStefano, Dejea, Christine M, Fathi, Payam, Chen, Jie, Finard, Benjamin B, Tam, Ada J, McAllister, Florencia, Fan, Hongni, Wu, Xinqun, Ganguly, Sudipto, Lebid, Andriana, Metz, Paul, Van Meerbeke, Sara W, Huso, David L, Wick, Elizabeth C, Pardoll, Drew M, Wan, Fengyi, Wu, Shaoguang, Sears, Cynthia L, and Housseau, Franck
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Digestive Diseases ,Colo-Rectal Cancer ,Cancer ,Adenomatous Polyposis Coli Protein ,Animals ,Bacterial Toxins ,Bacteroides fragilis ,Carcinogenesis ,Cell Line ,Tumor ,Colon ,Colorectal Neoplasms ,Enzyme Activation ,Epithelial Cells ,Female ,Gene Deletion ,HT29 Cells ,Humans ,Inflammation ,Interleukin-17 ,Male ,Metalloendopeptidases ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myeloid Cells ,Receptors ,Interleukin-17 ,Receptors ,Interleukin-8B ,STAT3 Transcription Factor ,Transcription Factor RelA ,Nf-κB ,STAT-3 ,colorectal cancer ,inflammation ,mucosal immunology ,myeloid cells ,Microbiology ,Medical Microbiology ,Immunology ,Biochemistry and cell biology ,Medical microbiology - Abstract
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
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- 2018
5. Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
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Shin, Daniel Sanghoon, Zaretsky, Jesse M, Escuin-Ordinas, Helena, Garcia-Diaz, Angel, Hu-Lieskovan, Siwen, Kalbasi, Anusha, Grasso, Catherine S, Hugo, Willy, Sandoval, Salemiz, Torrejon, Davis Y, Palaskas, Nicolaos, Rodriguez, Gabriel Abril, Parisi, Giulia, Azhdam, Ariel, Chmielowski, Bartosz, Cherry, Grace, Seja, Elizabeth, Berent-Maoz, Beata, Shintaku, I Peter, Le, Dung T, Pardoll, Drew M, Diaz, Luis A, Tumeh, Paul C, Graeber, Thomas G, Lo, Roger S, Comin-Anduix, Begoña, and Ribas, Antoni
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Human Genome ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Antibodies ,Monoclonal ,Humanized ,Cell Line ,Tumor ,Colonic Neoplasms ,Drug Resistance ,Neoplasm ,Gene Expression Regulation ,Neoplastic ,Humans ,Interferon-gamma ,Janus Kinase 1 ,Janus Kinase 2 ,Melanoma ,Mutation ,Neoplasms ,Programmed Cell Death 1 Receptor ,Signal Transduction ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.SignificanceA key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.
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- 2017
6. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade
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Fu, Juan, Kanne, David B, Leong, Meredith, Glickman, Laura Hix, McWhirter, Sarah M, Lemmens, Edward, Mechette, Ken, Leong, Justin J, Lauer, Peter, Liu, Weiqun, Sivick, Kelsey E, Zeng, Qi, Soares, Kevin C, Zheng, Lei, Portnoy, Daniel A, Woodward, Joshua J, Pardoll, Drew M, Dubensky, Thomas W, and Kim, Young
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Immunization ,Biotechnology ,Vaccine Related ,Animals ,Antineoplastic Agents ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Cell Line ,Tumor ,Cytosol ,Dendritic Cells ,Female ,Humans ,Interferon-gamma ,Ligands ,Membrane Proteins ,Mice ,Mice ,Inbred BALB C ,Mice ,Inbred C3H ,Mice ,Inbred C57BL ,Monocytes ,NF-kappa B ,Neoplasm Transplantation ,Phosphates ,Programmed Cell Death 1 Receptor ,Protein Serine-Threonine Kinases ,STAT6 Transcription Factor ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.
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- 2015
7. Consensus nomenclature for CD8+ T cell phenotypes in cancer
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Apetoh, Lionel, Smyth, Mark J, Drake, Charles G, Abastado, Jean-Pierre, Apte, Ron N, Ayyoub, Maha, Blay, Jean-Yves, Bonneville, Marc, Butterfield, Lisa H, Caignard, Anne, Castelli, Chiara, Cavallo, Federica, Celis, Esteban, Chen, Lieping, Colombo, Mario P, Comin-Anduix, Begoña, Coukos, Georges, Dhodapkar, Madhav V, Dranoff, Glenn, Frazer, Ian H, Fridman, Wolf-Hervé, Gabrilovich, Dmitry I, Gilboa, Eli, Gnjatic, Sacha, Jäger, Dirk, Kalinski, Pawel, Kaufman, Howard L, Kiessling, Rolf, Kirkwood, John, Knuth, Alexander, Liblau, Roland, Lotze, Michael T, Lugli, Enrico, Marincola, Francesco, Melero, Ignacio, Melief, Cornelis J, Mempel, Thorsten R, Mittendorf, Elizabeth A, Odun, Kunle, Overwijk, Willem W, Palucka, Anna Karolina, Parmiani, Giorgio, Ribas, Antoni, Romero, Pedro, Schreiber, Robert D, Schuler, Gerold, Srivastava, Pramod K, Tartour, Eric, Valmori, Danila, van der Burg, Sjoerd H, van der Bruggen, Pierre, van den Eynde, Benoît J, Wang, Ena, Zou, Weiping, Whiteside, Theresa L, Speiser, Daniel E, Pardoll, Drew M, Restifo, Nicholas P, and Anderson, Ana C
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,anergy ,anticancer immunity ,CD8(+) T cells ,cytotoxicity ,exhaustion ,effector ,IFN gamma ,senescence ,stemness ,CD8+ T cells ,IFNγ ,Oncology and carcinogenesis - Abstract
Whereas preclinical investigations and clinical studies have established that CD8+ T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8+ T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8+ T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8+ T cell immunity, leading to the emergence of dysfunctional CD8+ T cells. The existence of different types of CD8+ T cells in cancer calls for a more precise definition of the CD8+ T cell immune phenotypes in cancer and the abandonment of the generic terms "pro-tumor" and "antitumor." Based on recent studies investigating the functions of CD8+ T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8+ T cells in cancer.
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- 2015
8. Direct Visualization of Antigen-Specific T Cells: HTLV-1 Tax11-19-Specific CD8 + T Cells are Activated in Peripheral Blood and Accumulate in Cerebrospinal Fluid from HAM/TSP Patients
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Greten, Tim F., Slansky, Jill E., Kubota, Ryuji, Soldan, Samantha S., Jaffee, Elizabeth M., Leist, Thomas P., Pardoll, Drew M., Jacobson, Steven, and Schneck, Jonathan P.
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- 1998
9. The Immunodominant Major Histocompatibility Complex Class I-Restricted Antigen of a Murine Colon Tumor Derives from an Endogenous Retroviral Gene Product
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Huang, Alex Y., Gulden, Pamela H., Woods, Amina S., Thomas, Matthew C., Tong, Caryn D., Wang, Wei, Engelhard, Victor H., Pasternack, Gary, Cotter, Robert, Hunt, Donald, Pardoll, Drew M., and Jaffee, Elizabeth M.
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- 1996
10. Murine fecal microbiota transfer models selectively colonize human microbes and reveal transcriptional programs associated with response to neoadjuvant checkpoint inhibitors
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Fyza Y. Shaikh, Joell J. Gills, Fuad Mohammad, James R. White, Courtney M. Stevens, Hua Ding, Juan Fu, Ada Tam, Richard L. Blosser, Jada C. Domingue, Tatianna C. Larman, Jamie E. Chaft, Jonathan D. Spicer, Joshua E. Reuss, Jarushka Naidoo, Patrick M. Forde, Sudipto Ganguly, Franck Housseau, Drew M. Pardoll, and Cynthia L. Sears
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Cancer Research ,Lung Neoplasms ,Immunology ,Reproducibility of Results ,Fecal Microbiota Transplantation ,Neoadjuvant Therapy ,Article ,Mice ,Oncology ,Carcinoma, Non-Small-Cell Lung ,RNA, Ribosomal, 16S ,Animals ,Humans ,Immunology and Allergy - Abstract
Human gut microbial species found to associate with clinical responses to immune checkpoint inhibitors (ICIs) are often tested in mice using fecal microbiota transfer (FMT), wherein tumor responses in recipient mice may recapitulate human responses to ICI treatment. However, many FMT studies have reported only limited methodological description, details of murine cohorts, and statistical methods. To investigate the reproducibility and robustness of gut microbial species that impact ICI responses, we performed human to germ-free mouse FMT using fecal samples from patients with non-small cell lung cancer who had a pathological response or nonresponse after neoadjuvant ICI treatment. R-FMT mice yielded greater anti-tumor responses in combination with anti-PD-L1 treatment compared to NR-FMT, although the magnitude varied depending on mouse cell line, sex, and individual experiment. Detailed investigation of post-FMT mouse microbiota using 16S rRNA amplicon sequencing, with models to classify and correct for biological variables, revealed a shared presence of the most highly abundant taxa between the human inocula and mice, though low abundance human taxa colonized mice more variably after FMT. Multiple Clostridium species also correlated with tumor outcome in individual anti-PD-L1-treated R-FMT mice. RNAseq analysis revealed differential expression of T and NK cell-related pathways in responding tumors, irrespective of FMT source, with enrichment of these cell types confirmed by immunohistochemistry. This study identifies several human gut microbial species that may play a role in clinical responses to ICIs and suggests attention to biological variables is needed to improve reproducibility and limit variability across experimental murine cohorts.
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- 2022
11. High-dimensional Cytometry (ExCYT) and Mass Spectrometry of Myeloid Infiltrate in Clinically Localized Clear Cell Renal Cell Carcinoma Identifies Novel Potential Myeloid Targets for Immunotherapy
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David J. Clark, Michael H. Johnson, Hui Zhang, John-William Sidhom, Sudipto Ganguly, Debebe Theodros, Drew M. Pardoll, Ada J. Tam, Richard L. Blosser, Li Jun Chen, Phillip M. Pierorazio, Thomas R. Nirschl, Benjamin Murter, Jelani C. Zarif, and Zeyad Schwen
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Myeloid ,medicine.medical_treatment ,clear cell renal cell carcinoma ,Biochemistry ,Peripheral blood mononuclear cell ,Mass Spectrometry ,Analytical Chemistry ,immunology ,03 medical and health sciences ,Immune system ,Tandem Mass Spectrometry ,Renal cell carcinoma ,Biomarkers, Tumor ,Tumor Microenvironment ,medicine ,Humans ,Carcinoma, Renal Cell ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Tumor microenvironment ,business.industry ,Research ,030302 biochemistry & molecular biology ,kidney cancer ,Genomics ,Immunotherapy ,peripheral blood mononuclear cells ,Flow Cytometry ,Prognosis ,medicine.disease ,Kidney Neoplasms ,macrophages ,ExCYT ,Gene Expression Regulation, Neoplastic ,Clear cell renal cell carcinoma ,medicine.anatomical_structure ,clinical proteomics ,Leukocytes, Mononuclear ,Cancer research ,Leukocyte Common Antigens ,monocytes ,business ,Cytometry ,Signal Transduction - Abstract
Although the focus of the role of cancer immunotherapy has been in advanced disease states, we sought to investigate changes to the immune infiltrate of early, clinically localized clear cell Renal Cell Carcinoma (ccRCC). Using orthogonal approaches including Mass Spectrometry on immune cell infiltrates, we report numerous alterations that provide new insight into the biology of treatment-naïve ccRCC and identification of novel targets that may prove to be clinically impactful., Graphical Abstract Highlights Using ExCYT, genomics, and Mass Spectrometry, we were able to uncover immune cell marker alterations that provide new insight into the biology of early stage ccRCC. Among the CD45+ population, we observed a high level of myeloid cell infiltration in treatment-naïve ccRCC tissues., Renal Cell Carcinoma (RCC) is one of the most commonly diagnosed cancers worldwide with research efforts dramatically improving understanding of the biology of the disease. To investigate the role of the immune system in treatment-naïve clear cell Renal Cell Carcinoma (ccRCC), we interrogated the immune infiltrate in patient-matched ccRCC tumor samples, benign normal adjacent tissue (NAT) and peripheral blood mononuclear cells (PBMCs isolated from whole blood, focusing our attention on the myeloid cell infiltrate. Using flow cytometric, MS, and ExCYT analysis, we discovered unique myeloid populations in PBMCs across patient samples. Furthermore, normal adjacent tissues and ccRCC tissues contained numerous myeloid populations with a unique signature for both tissues. Enrichment of the immune cell (CD45+) fraction and subsequent gene expression analysis revealed a number of myeloid-related genes that were differentially expressed. These data provide evidence, for the first time, of an immunosuppressive and pro-tumorigenic role of myeloid cells in early, clinically localized ccRCC. The identification of a number of immune proteins for therapeutic targeting provides a rationale for investigation into the potential efficacy of earlier intervention with single-agent or combination immunotherapy for ccRCC.
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- 2020
12. 836 Murine fecal microbiota transfer models colonize human microbes selectively and reveal transcriptional pathways associated with response to neoadjuvant checkpoint inhibitors
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Fuad Mohammad, Joell J. Gills, Patrick M. Forde, Tatianna Larman, Juan Fu, Courtney Stevens, James A. White, Fyza Y. Shaikh, Drew M. Pardoll, Cynthia L. Sears, Sudipto Ganguly, Ada Tam, Franck Housseau, Jarushka Naidoo, Richard L. Blosser, and Hua Ding
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Pharmacology ,Cancer Research ,Oncology ,Immune checkpoint inhibitors ,Immunology ,Molecular Medicine ,Immunology and Allergy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Fecal microbiota ,Biology ,RC254-282 ,Cell biology - Abstract
BackgroundHuman gut microbial species found to associate with clinical responses to immune checkpoint inhibitors (ICIs) are often tested in murine models using fecal microbiota transfer (FMT), wherein tumor responses in recipient mice may recapitulate human responses to ICI treatment. However, many FMT studies have reported only limited methodological description, including identification of colonizing species associated with murine outcomes, details of murine cohorts, and statistical methods. Thus, the reproducibility and robustness of ICI murine models remain uncertain.MethodsTo investigate gut microbial species that impact ICI responses, we performed human to germ-free (GF) mouse FMT using pre-treatment stools from a pathologic lung cancer responder (R) and a pathologic lung cancer non-responder (NR) after neoadjuvant anti-PD-1 and anti-CTLA4 treatment, followed by implantation of the mice with syngeneic tumors and anti-PD-L1 treatment. Cohorts of GF mice varied by sex, age and syngeneic cell line implanted. To identify relevant microbes, murine tumor progressors (MT-P) and non-progressors (MT-NP) to anti-PD-L1 were classified based on tumor growth curves, 16S rRNA sequencing of human and mouse stools was performed, and data was statistically corrected for mouse characteristics using a generalized linear model. RNA sequencing was performed to assess transcriptional changes in murine tumors.ResultsR-FMT mice yielded a greater anti-tumor response in combination with anti-PD-L1 treatment compared to NR-FMT, although the magnitude varied depending on the mouse cell line, sex, and individual experiment. Microbiota analysis revealed a shared presence of the most highly abundant taxa between the human inocula and mice, however low abundance human taxa colonized mice more variably after FMT. Multiple Clostridium species correlated with tumor outcome in individual anti-PD-L1-treated R-FMT mice. RNAseq analysis revealed differential expression of T cell and NK cell-related pathways in responding tumors, irrespective of FMT source, and enrichment of these cell types were confirmed by immunohistochemistry.ConclusionsThis study identifies several human intestinal microbial species that may play a role in clinical responses to ICIs and suggests attention to biological variables is needed to improve reproducibility and limit variability across experimental murine models.Ethics ApprovalAll studies in this abstract have been approved by Johns Hopkins University Animal Care and Use and Johns Hopkins Medicine Institutional Review Board.
- Published
- 2021
13. Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes
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Gady Cojocaru, Ada J. Tam, Nicolas J. Llosa, Elizabeth D. Thompson, Drew M. Pardoll, Nicholas Siegel, Carol D. Morris, Daniel S. Rhee, Robert A. Anders, John A. Ligon, Teniola Oke, Brian H. Ladle, Aditya Suru, Christine A. Pratilas, Adam S. Levin, Emily Han-Chung Hsiue, Richard L. Blosser, Christian F. Meyer, Franck Housseau, Wei Fu, Woonyoung Choi, Megan H. Fong, and David J. McConkey
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,sarcoma ,medicine.medical_treatment ,Lymphocyte Activation ,0302 clinical medicine ,Tumor-Associated Macrophages ,Immunotherapy Biomarkers ,Tumor Microenvironment ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Electronic Health Records ,RC254-282 ,Osteosarcoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Progression-Free Survival ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,translational medical research ,Molecular Medicine ,Cytokines ,Immunotherapy ,pediatrics ,T cell ,Immunology ,Bone Neoplasms ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Antigen ,Biomarkers, Tumor ,Humans ,Retrospective Studies ,Pharmacology ,Tumor microenvironment ,business.industry ,Myeloid-Derived Suppressor Cells ,Macrophage Activation ,Immune Checkpoint Proteins ,Immune checkpoint ,030104 developmental biology ,Cancer research ,business ,Transcriptome ,CD8 - Abstract
BackgroundCurrent therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.Methods66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung ‘PM interface’ and ‘PM interior’ regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection.ResultsIHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS.ConclusionsOsteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.
- Published
- 2021
14. Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
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Qingfeng Zhu, Haidan Guo, Franco Verde, Hao Wang, Patrick M. Forde, Dung T. Le, Sune Justesen, Teniola Oke, Hongni Fan, Prerna Suri, Leslie Cope, Ludmila Danilova, Janis M. Taube, Anas H. Awan, Franck Housseau, Jennifer N. Durham, Hok Yee Chan, Nickolas Papadopoulos, Elizabeth D. Thompson, Bjarne Bartlett, Robert A. Anders, Nicholas Siegel, Victor E. Velculescu, Kellie N. Smith, John-William Sidhom, Laveet K. Aulakh, Kristen A. Marrone, Valsamo Anagnostou, Cynthia L. Sears, Joanne Riemer, Drew M. Pardoll, Luis A. Diaz, Brandon Luber, Ada J. Tam, Bert Vogelstein, Tricia R. Cottrell, Nicolas J. Llosa, Kenneth W. Kinzler, Julie R. Brahmer, William H. Sharfman, and Jarushka Naidoo
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Colorectal cancer ,T cell ,T-Lymphocytes ,Immunology ,Cell ,T cells ,Case Report ,Disease ,lcsh:RC254-282 ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Predictive biomarkers ,Checkpoint blockade ,Carcinoma, Non-Small-Cell Lung ,medicine ,Immunology and Allergy ,Humans ,Oncogene ,Aged ,Pharmacology ,Neoantigens ,business.industry ,Correction ,Oncogenes ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Primary tumor ,3. Good health ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,Nivolumab ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Molecular Medicine ,DNA mismatch repair ,Female ,business ,Colorectal Neoplasms - Abstract
Background Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently. Case presentation We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations – BRAF-N581I in the NSCLC and AKT1-E17K in the CRC – years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment. Conclusions These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade. Electronic supplementary material The online version of this article (10.1186/s40425-018-0492-x) contains supplementary material, which is available to authorized users.
- Published
- 2019
15. Non-toxigenic Bacteroides fragilis (NTBF) administration reduces bacteria-driven chronic colitis and tumor development independent of polysaccharide A
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June L. Chan, Shaoguang Wu, Ada J. Tam, Abby L. Geis, Talles A.M. Gomes, Franck Housseau, Hongni Fan, Xinqun Wu, Drew M. Pardoll, Hua Ding, Cynthia L. Sears, Gabrielle V. Chan, Hao Wang, Sarah E. Beck, and Liam Chung
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Lipopolysaccharides ,0301 basic medicine ,Carcinogenesis ,Colorectal cancer ,Adenomatous Polyposis Coli Protein ,Immunology ,medicine.disease_cause ,Inflammatory bowel disease ,Article ,Microbiology ,Bacteroides fragilis ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Intestinal Mucosa ,Colitis ,Cells, Cultured ,Mice, Knockout ,biology ,business.industry ,Interleukin-17 ,Inflammatory Bowel Diseases ,medicine.disease ,biology.organism_classification ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Trinitrobenzenesulfonic Acid ,Th17 Cells ,Colorectal Neoplasms ,business ,Bacteria ,030215 immunology - Abstract
Polysaccharide A (PSA), an immunogenic capsular component of non-toxigenic Bacteroides fragilis (NTBF) strain NCTC 9343, is reported to promote mucosal immune development and suppress colitis. Contrastingly, enterotoxigenic Bacteroides fragilis (ETBF) is highly associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), rapidly inducing IL-17-dependent murine colitis and tumorigenesis. In specific-pathogen-free (SPF) C57BL/6 wild-type (WT) and multiple intestinal neoplasia (MinApc716+/-) mice, we show that sequential treatment of the NTBF strain, 9343, followed by the ETBF strain, 86-5443-2-2 (86), diminished colitis and tumorigenesis. Mice treated simultaneously with 9343 and 86 exhibited both severe colitis and tumorigenesis. Abrogated disease severity in sequentially treated mice was attributed to 9343 strain dominance and decreased IL-17A, but 86 colonization prior to or simultaneous with 9343 mitigated the anti-inflammatory effect of 9343. Remarkably, 9343-mediated protection was independent of PSA, as sequentially treated mice receiving ΔPSA 9343 exhibited similar protection. Further, SPF WT and Min mice colonized with PSA-competent or PSA-deficient 9343 exhibited similar IL-10, IL-17, and IFN-γ responses. Treatment of 86-colonized mice with 9343 failed to disrupt 86 pathogenesis. Our findings demonstrate that 9343 colonization, independent of PSA, offers prophylaxis against colitis-inducing 86 but may not be a valid therapy once colitis is established.
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- 2019
16. Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures
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Teniola Oke, Thomas B. Schaffer, Evan J. Lipson, Dung T. Le, Christian F. Meyer, Lingling Chen, John Mc Mahon Gross, Laurene S. Cheung, Jillian T. Ngo, Nicolas J. Llosa, Janis M. Taube, Holly Kemberling, Karim Boudadi, John-William Sidhom, Robert A. Anders, Drew M. Pardoll, and Luis A. Diaz
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0301 basic medicine ,Male ,Cancer Research ,sarcoma ,medicine.medical_treatment ,Immunology ,Programmed Cell Death 1 Receptor ,Case Report ,medicine.disease_cause ,Undifferentiated Pleomorphic Sarcoma ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Immunology and Allergy ,Humans ,RC254-282 ,Pharmacology ,Mutation ,Tumor microenvironment ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell Differentiation ,Immunotherapy ,Middle Aged ,medicine.disease ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Scalp ,tumor biomarkers ,Cancer research ,Molecular Medicine ,Sarcoma ,business ,CD8 - Abstract
Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.
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- 2021
17. Functional characterization of CD4+ T-cell receptors cross-reactive for SARS-CoV-2 and endemic coronaviruses
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Drew M. Pardoll, Bezawit A. Woldemeskel, Franco R. D'Alessio, Hongkai Ji, Emily Han-Chung Hsiue, Kellie N. Smith, Justina X. Caushi, Jiajia Zhang, Shibin Zhou, Jonathan D. Powell, Alvaro A. Ordonez, Rufiaat Rashid, Arbor G. Dykema, Elizabeth A. Thompson, Joel N. Blankson, Boyang Zhang, Caroline C. Garliss, Dilshad Choudhury, Sadhana Bom, Sampriti Thapa, Laurene S. Cheung, Dipika Singh, Andrea L. Cox, Andrew Pekosz, Abena K. Kwaa, Katherine Cascino, Srinivasan Yegnasubramanian, and Luis Aparicio
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Adult ,CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,viruses ,medicine.medical_treatment ,T cell ,Receptors, Antigen, T-Cell ,Epitopes, T-Lymphocyte ,chemical and pharmacologic phenomena ,Context (language use) ,Cross Reactions ,Biology ,Jurkat cells ,Jurkat Cells ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Antigen ,medicine ,Humans ,Avidity ,Receptor ,Aged ,SARS-CoV-2 ,T-cell receptor ,COVID-19 ,General Medicine ,Middle Aged ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Female ,Clinical Medicine ,Immunologic Memory - Abstract
BACKGROUND: Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2. METHODS: We used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2–unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system. RESULTS: Memory CD4(+) T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2–specific proliferation in vitro relative to monospecific CD4(+) T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC. CONCLUSIONS: Our data confirm, for what we believe is the first time, the existence of unique memory CD4(+) T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients. FUNDING: NIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.
- Published
- 2021
18. Bispecific antibodies targeting mutant RAS neoantigens
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Qing Wang, Suman Paul, Sandra B. Gabelli, Liu Qiang, Emily Han-Chung Hsiue, Kenneth W. Kinzler, Nickolas Papadopoulos, Shibin Zhou, Yana Li, Jacqueline Douglass, Annika Schaefer, Alexander H. Pearlman, Evangeline Watson, Brian J. Mog, Andrew D. Skora, Sarah R. DiNapoli, Katharine M. Wright, Michael S. Hwang, Maximilian F. Konig, Michael B. Murphy, Marco Dal Molin, Chetan Bettegowda, Drew M. Pardoll, Bert Vogelstein, Michelle S. Miller, and P. Aitana Azurmendi
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0301 basic medicine ,Phage display ,T cell ,Immunology ,Mutant ,Context (language use) ,Human leukocyte antigen ,Cross Reactions ,Biology ,Lymphocyte Activation ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,HLA Antigens ,T-Lymphocyte Subsets ,Antibodies, Bispecific ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Gene ,General Medicine ,Peptide Fragments ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer cell ,ras Proteins ,Cancer research ,biology.protein ,Mutant Proteins ,Antibody ,Protein Binding - Abstract
Mutations in the RAS oncogenes occur in multiple cancers, and ways to target these mutations has been the subject of intense research for decades. Most of these efforts are focused on conventional small-molecule drugs rather than antibody-based therapies because the RAS proteins are intracellular. Peptides derived from recurrent RAS mutations, G12V and Q61H/L/R, are presented on cancer cells in the context of two common human leukocyte antigen (HLA) alleles, HLA-A3 and HLA-A1, respectively. Using phage display, we isolated single-chain variable fragments (scFvs) specific for each of these mutant peptide-HLA complexes. The scFvs did not recognize the peptides derived from the wild-type form of RAS proteins or other related peptides. We then sought to develop an immunotherapeutic agent that was capable of killing cells presenting very low levels of these RAS-derived peptide-HLA complexes. Among many variations of bispecific antibodies tested, one particular format, the single-chain diabody (scDb), exhibited superior reactivity to cells expressing low levels of neoantigens. We converted the scFvs to this scDb format and demonstrated that they were capable of inducing T cell activation and killing of target cancer cells expressing endogenous levels of the mutant RAS proteins and cognate HLA alleles. CRISPR-mediated alterations of the HLA and RAS genes provided strong genetic evidence for the specificity of the scDbs. Thus, this approach could be applied to other common oncogenic mutations that are difficult to target by conventional means, allowing for more specific anticancer therapeutics.
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- 2021
19. Engineering an Intracellular Pathway for Major Histocompatibility Complex Class II Presentation of Antigens
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Wu, Tzyy-Choou, Guarnieri, Frank G., Staveley-O'Carroll, Kevin F., Viscidi, Raphael P., Levitsky, Hyam I., Hedrick, Lora, Cho, Kathleen R., August, J. Thomas, and Pardoll, Drew M.
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- 1995
20. Molecular Events in the Induction of a Nonresponsive State in Interleukin 2-Producing Helper T-Lymphocyte Clones
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Jenkins, Marc K., Pardoll, Drew M., Mizuguchi, Junichiro, Chused, Thomas M., and Schwartz, Ronald H.
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- 1987
21. IMMU-27. SINGLE CELL RNA-SEQUENCING IDENTIFIES NOVEL BONE MARROW DERIVED MYELOID CELLS IN GLIOBLASTOMA ASSOCIATED WITH TUMOR AGGRESSION
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John Choi, Christopher Cherry, Vasan Yegnasubramanian, Drew M. Pardoll, Hao Zhang, Michael Lim, Sadhana Bom, Christina Jackson, and Jennifer H. Elisseeff
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Cancer Research ,Aggression ,Cell ,Immunology ,RNA ,Biology ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Myeloid cells ,medicine ,Cancer research ,Neurology (clinical) ,Bone marrow ,medicine.symptom ,Glioblastoma - Abstract
BACKGROUND Glioma associated myeloid cells (GAMs) can be induced to adopt an immunosuppressive phenotype that can lead to inhibition of anti-tumor responses in glioblastoma (GBM). Understanding the composition and phenotypes of GAMs is essential to modulating the myeloid compartment as a therapeutic adjunct to improve anti-tumor immune response. METHODS We performed single-cell RNA-sequencing (sc-RNAseq) of 435,400 myeloid and tumor cells to identify transcriptomic and phenotypic differences in GAMs across glioma grades. We further correlated the heterogeneity of the GAM landscape with tumor cell transcriptomics to investigate interactions between GAMs and tumor cells. RESULTS sc-RNAseq revealed a diverse landscape of myeloid-lineage cells in gliomas with an increase in preponderance of bone marrow derived myeloid cells (BMDMs) with increasing tumor grade. We identified two populations of BMDMs unique to GBMs; Mac-1and Mac-2. Mac-1 demonstrates upregulation of immature myeloid gene signature and altered metabolic pathways. Mac-2 is characterized by expression of scavenger receptor MARCO. Pseudotime and RNA velocity analysis revealed the ability of Mac-1 to transition and differentiate to Mac-2 and other GAM subtypes. We further found that the presence of these two populations of BMDMs are associated with the presence of tumor cells with stem cell and mesenchymal features. Bulk RNA-sequencing data demonstrates that gene signatures of these populations are associated with worse survival in GBM. CONCLUSION We used sc-RNAseq to identify a novel population of immature BMDMs that is associated with higher glioma grades. This population exhibited altered metabolic pathways and stem-like potentials to differentiate into other GAM populations including GAMs with upregulation of immunosuppressive pathways. Our results elucidate unique interactions between BMDMs and GBM tumor cells that potentially drives GBM progression and the more aggressive mesenchymal subtype. Our discovery of these novel BMDMs have implications in new therapeutic targets in improving the efficacy of immune-based therapies in GBM.
- Published
- 2020
22. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer
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Daphne Wang, Taha Merghoub, Jarushka Naidoo, Jinny Ha, David R. Jones, Marianna Zahurak, Joseph C. Murray, Ben Levy, Kellie N. Smith, Stephen R. Broderick, Drew M. Pardoll, Suzanne L. Topalian, Jamie E. Chaft, Richard J. Battafarano, Valsamo Anagnostou, Errol L. Bush, Janis M. Taube, Victor E. Velculescu, Mara Lanis, Peter B. Illei, Matthew D. Hellmann, Malcolm V. Brock, Gary L. Rosner, Hok Yee Chan, James R. White, Franco Verde, Joshua E. Reuss, Caroline G. McCarthy, Patrick M. Forde, Tricia R. Cottrell, Stephen C. Yang, and Julie R. Brahmer
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Immunology ,Short Report ,Ipilimumab ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Immunology and Allergy ,Medicine ,tumor microenvironment ,Humans ,Lung cancer ,Adverse effect ,RC254-282 ,Aged ,Pharmacology ,clinical trials as topic ,business.industry ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,030104 developmental biology ,Nivolumab ,Tumor progression ,030220 oncology & carcinogenesis ,tumor biomarkers ,Molecular Medicine ,Female ,KRAS ,immunotherapy ,business ,medicine.drug - Abstract
BackgroundWe conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.MethodsPatients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.ResultsWhile the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.ConclusionsThough treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.
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- 2020
23. YAP Attenuates CD8 T Cell-Mediated Anti-tumor Response
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Andriana Lebid, Liam Chung, Drew M. Pardoll, and Fan Pan
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,tumor ,Immunology ,Cell Cycle Proteins ,Biology ,CD8-Positive T-Lymphocytes ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Downregulation and upregulation ,Neoplasms ,medicine ,Tumor Microenvironment ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Adaptor Proteins, Signal Transducing ,Original Research ,Antitumor activity ,Hippo signaling pathway ,Tumor microenvironment ,Cancer ,YAP-Signaling Proteins ,immunesuppression ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,CD8 T cell ,Transcriptional Coactivator ,Cancer cell ,Cancer research ,YAP ,hippo ,lcsh:RC581-607 ,030215 immunology ,Transcription Factors - Abstract
YAP is a transcriptional coactivator of the Hippo signaling pathway that has largely been studied for its role in the regulation of organ size during development. Several studies have shown that YAP is upregulated in cancer cells, and more recently in the T regulatory (Treg) subset of CD4+ cells. These observations suggest that the transcriptional co-activator may promote tumor persistence and progression. Here, we report that YAP also plays an immunoinhibitory role in CD8 T cells, especially in activated cytotoxic cells usually found in the tumor microenvironment. Our findings add further rationale for the development and use of pharmacologic inhibitors of YAP to treat cancer.
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- 2020
24. Mechanisms regulating PD-L1 expression on tumor and immune cells
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George A. Crabill, Fan Pan, Shuming Chen, Drew M. Pardoll, Tracee L. McMiller, Suzanne L. Topalian, Theresa S. Pritchard, and Ping Wei
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PD-L1 ,0301 basic medicine ,Cancer Research ,Small interfering RNA ,medicine.medical_treatment ,Immunology ,Cell ,Cancer immunotherapy ,Biology ,lcsh:RC254-282 ,B7-H1 Antigen ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Neoplasms ,Transcription factors ,medicine ,Humans ,Immunology and Allergy ,STAT3 ,Interferon gamma ,Pharmacology ,Tumor microenvironment ,Gene knockdown ,Interleukins ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Cytokines ,Molecular Medicine ,Research Article - Abstract
Background The PD-1/PD-L1 checkpoint is a central mediator of immunosuppression in the tumor immune microenvironment (TME) and is primarily associated with IFN-g signaling. To characterize other factors regulating PD-L1 expression on tumor and/or immune cells, we investigated TME-resident cytokines and the role of transcription factors in constitutive and cytokine-induced PD-L1 expression. Methods Thirty-four cultured human tumor lines [18 melanomas (MEL), 12 renal cell carcinomas (RCC), 3 squamous cell carcinomas of the head and neck (SCCHN), and 1 non-small-cell lung carcinoma (NSCLC)] and peripheral blood monocytes (Monos) were treated with cytokines that we detected in the PD-L1+ TME by gene expression profiling, including IFN-g, IL-1a, IL-10, IL-27 and IL-32g. PD-L1 cell surface protein expression was detected by flow cytometry, and mRNA by quantitative real-time PCR. Total and phosphorylated STAT1, STAT3, and p65 proteins were detected by Western blotting, and the genes encoding these proteins were knocked down with siRNAs. Additionally, the proximal promoter region of PDL1 (CD274) was sequenced in 33 cultured tumors. Results PD-L1 was constitutively expressed on 1/17 cultured MELs, 8/11 RCCs, 3/3 SCCHNs, and on Monos. Brief IFN-g exposure rapidly induced PD-L1 on all tumor cell lines and Monos regardless of constitutive PD-L1 expression. PD-L1 mRNA levels were associated with protein expression, which was diminished by exposure to transcriptional inhibitors. siRNA knockdown of STAT1 but not STAT3 reduced IFN-g- and IL-27-induced PD-L1 protein expression on tumor cells. In contrast, STAT3 knockdown in Monos reduced IL-10-induced PD-L1 protein expression, and p65 knockdown in tumor cells reduced IL-1a-induced PD-L1 expression. Notably, constitutive PD-L1 expression was not affected by knocking down STAT1, STAT3, or p65. Differential effects of IFN-g, IL-1a, and IL-27 on individual tumor cell lines were not due to PDL1 promoter polymorphisms. Conclusions Multiple cytokines found in an immune-reactive TME may induce PD-L1 expression on tumor and/or immune cells through distinct signaling mechanisms. Factors driving constitutive PD-L1 expression were not identified in this study. Understanding complex mechanisms underlying PD-L1 display in the TME may allow treatment approaches mitigating expression of this immunosuppressive ligand, to enhance the impact of PD-1 blockade.
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- 2019
25. TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors
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Meredith L. Leong, Laura Hix Glickman, Ali Ghasemzadeh, Kelsey E. Sivick, Drew M. Pardoll, Andrew B. Sharabi, Thomas W. Dubensky, Debebe Theodros, Brian Francica, Sarah M. McWhirter, Gabrielle L. Reiner, Ariel E. Marciscano, Charles G. Drake, and Anthony L. Desbien
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0301 basic medicine ,Cancer Research ,Stromal cell ,Immunology ,Melanoma, Experimental ,Antigen-Presenting Cells ,Antineoplastic Agents ,Radiation Tolerance ,Article ,Mice ,Necrosis ,03 medical and health sciences ,Immune system ,Bone Marrow ,Cell Line, Tumor ,Neoplasms ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Antigen-presenting cell ,Mice, Knockout ,Tumor microenvironment ,Tumor Necrosis Factor-alpha ,business.industry ,Membrane Proteins ,Interferon-beta ,Acquired immune system ,Immunity, Innate ,Tumor Burden ,Disease Models, Animal ,Sting ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Cytokines ,Female ,Tumor necrosis factor alpha ,Bone marrow ,Nucleotides, Cyclic ,Stromal Cells ,business ,Signal Transduction - Abstract
The cGAS–STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow–derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422–33. ©2018 AACR.
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- 2018
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26. Transcriptional Mechanisms of Resistance to Anti–PD-1 Therapy
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Leslie Cope, Nadeem Riaz, Christine A. Iacobuzio-Donahue, Janis M. Taube, Barry S. Taylor, Ralph H. Hruban, Suzanne L. Topalian, Jinshui Fan, Evan J. Lipson, Genevieve J. Kaunitz, Maria Libera Ascierto, Timothy A. Chan, Zachary A. Kohutek, David B. Solit, Alvin Makohon-Moore, Vladimir Makarov, Tricia R. Cottrell, Tracee L. McMiller, Alexander V. Favorov, Alan E. Berger, and Drew M. Pardoll
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0301 basic medicine ,Cancer Research ,DNA Copy Number Variations ,Programmed Cell Death 1 Receptor ,Disease ,Drug resistance ,Biology ,Somatic evolution in cancer ,Article ,Clonal Evolution ,03 medical and health sciences ,Exome Sequencing ,Gene expression ,medicine ,Humans ,Neoplasm Metastasis ,Melanoma ,Exome sequencing ,Regulation of gene expression ,Cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Immunology - Abstract
Purpose: To explore factors associated with response and resistance to anti–PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response. Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy. Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function. Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti–PD-1 outcomes. Clin Cancer Res; 23(12); 3168–80. ©2017 AACR. See related commentary by Wilmott et al., p. 2921
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- 2017
27. Long-Term Culture of Self-renewing Pancreatic Progenitors Derived from Human Pluripotent Stem Cells
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Simon M. Cool, Lawrence W. Stanton, Mohammad Shboul, Simon Denil, Drew M. Titmarsh, Giulia Rancati, Justin J. Cooper-White, Ee Kim Tan, Jamie Trott, Sheena Ong, Bruno Reversade, Maybelline Giam, Jiaxu Wang, Michelle Eio, N. Ray Dunn, Cheng Kit Wong, Lee Kong Chian School of Medicine (LKCMedicine), and School of Biological Sciences
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0301 basic medicine ,Cellular differentiation ,Mice, SCID ,Culture Conditions ,Kidney ,self-renewal ,Biochemistry ,Pancreatic Progenitors ,Mice ,Mice, Inbred NOD ,Insulin-Secreting Cells ,Insulin ,Cell Self Renewal ,β cell differentiation ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Stem Cells ,Cell Differentiation ,SOX9 Transcription Factor ,Cell biology ,Endothelial stem cell ,medicine.anatomical_structure ,tissue stem cells ,PDX1 ,Stem cell ,lcsh:Medicine (General) ,Pancreas ,Pluripotent Stem Cells ,Transplantation, Heterologous ,Down-Regulation ,Biology ,Article ,Cell Line ,03 medical and health sciences ,pancreatic development ,Directed differentiation ,culture conditions ,Genetics ,medicine ,Animals ,Humans ,Progenitor cell ,pancreatic progenitors ,Homeodomain Proteins ,directed differentiation ,Feeder Cells ,Cell Biology ,030104 developmental biology ,lcsh:Biology (General) ,Immunology ,Trans-Activators ,Developmental Biology - Abstract
Summary Pluripotent stem cells have been proposed as an unlimited source of pancreatic β cells for studying and treating diabetes. However, the long, multi-step differentiation protocols used to generate functional β cells inevitably exhibit considerable variability, particularly when applied to pluripotent cells from diverse genetic backgrounds. We have developed culture conditions that support long-term self-renewal of human multipotent pancreatic progenitors, which are developmentally more proximal to the specialized cells of the adult pancreas. These cultured pancreatic progenitor (cPP) cells express key pancreatic transcription factors, including PDX1 and SOX9, and exhibit transcriptomes closely related to their in vivo counterparts. Upon exposure to differentiation cues, cPP cells give rise to pancreatic endocrine, acinar, and ductal lineages, indicating multilineage potency. Furthermore, cPP cells generate insulin+ β-like cells in vitro and in vivo, suggesting that they offer a convenient alternative to pluripotent cells as a source of adult cell types for modeling pancreatic development and diabetes., Highlights • Culture on 3T3 cells enables long-term self-renewal of human pancreatic progenitors • Proliferation requires EGF, FGF10, retinoic acid, and inhibition of Notch and TGF-β • Cultured progenitors upregulate genes required for mitosis and telomere maintenance • Pancreatic duct and β-like cells are generated in vitro and in vivo, In this article, Trott and colleagues describe conditions that enable long-term self-renewal of pancreatic progenitors derived from human pluripotent stem cells. These cultured pancreatic progenitors can be expanded for at least 20 passages and are capable of differentiation into multiple pancreatic lineages, including β-like cells, both in vitro and in vivo.
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- 2017
28. Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
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Jillian Phallen, Malcolm V. Brock, Patrick M. Forde, Stephen B. Baylin, Cynthia A. Zahnow, Theresa Zhang, Peter B. Illei, Violeta Beleva Guthrie, Victor E. Velculescu, Vilmos Adleff, Valsamo Anagnostou, Qing Kay Li, James R. White, Neha Wali, Rohit Bhattacharya, Franco Verde, Kellie N. Smith, Robert B. Scharpf, Carolyn Hruban, Kristen Rodgers, Drew M. Pardoll, Rachel Karchin, Julie R. Brahmer, Christos S. Georgiades, Noushin Niknafs, Edward Gabrielson, Hyunseok Kang, Jarushka Naidoo, and William H. Sharfman
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Male ,0301 basic medicine ,Lung Neoplasms ,Cell cycle checkpoint ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Drug Resistance ,Cohort Studies ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Neoplasms ,Carcinoma, Non-Small-Cell Lung ,Receptors ,Monoclonal ,2.1 Biological and endogenous factors ,CTLA-4 Antigen ,Aetiology ,Non-Small-Cell Lung ,Lung ,Cancer ,integumentary system ,biology ,Lung Cancer ,Antibodies, Monoclonal ,Middle Aged ,Immunological ,Nivolumab ,Oncology ,5.1 Pharmaceuticals ,Antigen ,030220 oncology & carcinogenesis ,Female ,Immunotherapy ,Development of treatments and therapeutic interventions ,Antibody ,medicine.drug ,Adult ,Oncology and Carcinogenesis ,Receptors, Antigen, T-Cell ,Antineoplastic Agents ,Ipilimumab ,Article ,Antibodies ,03 medical and health sciences ,Immune system ,Antigens, Neoplasm ,Clinical Research ,medicine ,Humans ,Antigens ,Prevention ,Carcinoma ,Janus Kinase 1 ,Cell Cycle Checkpoints ,Janus Kinase 2 ,T-Cell ,Immune checkpoint ,Good Health and Well Being ,030104 developmental biology ,Drug Resistance, Neoplasm ,Mutation ,Immunology ,biology.protein ,Neoplasm ,Immunization - Abstract
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non–small cell lung cancer after initial response to immune checkpoint blockade with anti–PD-1 or anti–PD-1/anti–CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens. Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264–76. ©2017 AACR. See related commentary by Yang, p. 250. This article is highlighted in the In This Issue feature, p. 235
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- 2017
29. TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer
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Ali Ghasemzadeh, Andrea L. Cox, Thanh V. Huynh, Fan Pan, Suzanne Sebald, Drew M. Pardoll, Matthew E. Winter, Zachary T. Freeman, Benjamin V. Park, Se-Jin Lee, Alleluiah Rutebemberwa, Michael A. Chattergoon, and Jordana Steigner
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Biology ,Jurkat cells ,Article ,Transforming Growth Factor beta1 ,Jurkat Cells ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Downregulation and upregulation ,Cell Line, Tumor ,Neoplasms ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Smad3 Protein ,Tumor microenvironment ,Effector ,hemic and immune systems ,030104 developmental biology ,Cytokine ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Cytokines ,Signal transduction ,CD8 ,Signal Transduction - Abstract
Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFβ1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo. The PD-1hi subset seen in CD8+ TILs is absent in Smad3-deficient tumor-specific CD8+ TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity. In addition to TGFβ1′s previously known effects on T-cell function, our findings suggest that TGFβ1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFβ-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit antitumor immunity. Significance: Engagement of the coinhibitory receptor PD-1 or its ligand, PD-L1, dramatically inhibits the antitumor function of TILs within the TME. Our findings represent a novel immunosuppressive function of TGFβ and demonstrate that TGFβ1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs. Cancer Discov; 6(12); 1366–81. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1293
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- 2016
30. Autologous reconstitution of human cancer and immune system in vivo
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David L. Masica, Juan Fu, Vonn Walter, Rachel Karchin, Rupashree Sen, D. Neil Hayes, Young J. Kim, Drew M. Pardoll, and Christine H. Chung
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0301 basic medicine ,Myeloid ,medicine.medical_treatment ,Xenotransplantation ,CD34 ,Mice, Transgenic ,Mice, SCID ,Transplantation, Autologous ,STAT3 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Cancer immunotherapy ,Mice, Inbred NOD ,Cell Line, Tumor ,Neoplasms ,HLA-A2 Antigen ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Transgenes ,Immune response ,Tumor microenvironment ,Tumor-infiltrating lymphocytes ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Research Paper: Immunology ,Immunity ,autologous reconstitution ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,humanized mice ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Carcinoma, Squamous Cell ,Immunology and Microbiology Section ,Heterografts ,Bone marrow ,business ,head neck carcinoma ,Neoplasm Transplantation - Abstract
// Juan Fu 1 , Rupashree Sen 1 , David L. Masica 2 , Rachel Karchin 2,3 , Drew Pardoll 3 , Vonn Walter 4 , D. Neil Hayes 5 , Christine H. Chung 6 and Young J. Kim 3,7 1 Department of Otolaryngology - Head & Neck Surgery, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA 2 Department of Biomedical Engineering and The Institute for Computational Medicine, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA 3 Bloomberg-Kimmel Institute for Cancer Immunotherapy, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA 4 Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA 5 UNC Chapel Hill School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 6 Department of Head & Neck - Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA 7 Department of Otolaryngology - Head & Neck Surgery, VICC, Vanderbilt University Medical Center, Nashville, TN, USA Correspondence to: Young J. Kim, email: // Keywords : tumor microenvironment, autologous reconstitution, STAT3, humanized mice, head neck carcinoma, Immunology and Microbiology Section, Immune response, Immunity Received : August 19, 2016 Accepted : December 13, 2016 Published : December 19, 2016 Abstract Correlative studies from checkpoint inhibitor trials have indicated that better understanding of human leukocytic trafficking into the human tumor microenvironment can expedite the translation of future immune-oncologic agents. In order to directly characterize signaling pathways that can regulate human leukocytic trafficking into the tumor, we have developed a completely autologous xenotransplantation method to reconstitute the human tumor immune microenvironment in vivo. We were able to genetically mark the engrafted CD34+ bone marrow cells as well as the tumor cells, and follow the endogenous leukocytic infiltration into the autologous tumor. To investigate human tumor intrinsic factors that can potentially regulate the immune cells in our system, we silenced STAT3 signaling in the tumor compartment. As expected, STAT3 signaling suppression in the tumor compartment in these autologously reconstituted humanized mice showed increased tumor infiltrating lymphocytes and reduction of arginase-1 in the stroma, which were associated with slower tumor growth rate. We also used this novel system to characterize human myeloid suppressor cells as well as to screen novel agents that can alter endogenous leukocytic infiltration into the tumor. Taken together, we present a valuable method to study individualized human tumor microenvironments in vivo without confounding allogeneic responses.
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- 2016
31. IMMU-18. IMMUNOGENOMIC RESPONDER PHENOTYPE FROM A PHASE I TRIAL OF ANTI-LAG3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM
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Manmeet S Ahluwalia, Patrick Y. Wen, Kellie N. Smith, Stuart A. Grossman, Jiajia Zhang, Joy D. Fisher, Michael Lim, Arati Desai, Tobias Walbert, Burt Nabors, John Choi, Anna F. Piotrowski, Serena Desideri, Christina Jackson, Drew M. Pardoll, and Xiaobu Ye
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Cancer Research ,Chemokine ,LAG3 ,medicine.diagnostic_test ,Interferon type II ,biology ,business.industry ,medicine.medical_treatment ,Immunology ,CD137 ,Immunotherapy ,Peripheral blood mononuclear cell ,Flow cytometry ,Immunophenotyping ,Oncology ,medicine ,biology.protein ,Cancer research ,Neurology (clinical) ,business ,medicine.drug - Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are not uniformly effective in glioblastoma treatment. Immunogenomic determinants may identify patients who are most likely to benefit from these therapies. Therefore, we compared the immunogenomic phenotype of a responder to combination anti-LAG-3 and anti-PD-1 therapy to non-responders. METHODS We performed T cell receptor (TCR) sequencing and gene expression analysis on pre-treatment, post-chemoradiation, and post-immunotherapy tumor specimens of glioblastoma patients treated with anti-LAG3 in combination with anti-PD-1 after first recurrence (NCT02658981, ongoing). We evaluated T cell clonotypes and immunophenotype of serially collected peripheral blood mononuclear cells (PBMCs) during treatment using multi-parametric flow cytometry. RESULTS To date, six patients have been enrolled in the initial anti-LAG-3 and anti-PD-1 cohort. One patient demonstrated complete response, one had stable disease, and four had progressive disease by radiographic evaluation. The responder demonstrated substantially higher TCR clonality in the resected tumor at initial diagnosis compared to non-responders (mean 0.028 vs. 0.005). Shared tumor infiltrating clonotypes with pre-immunotherapy PBMCs exhibited an increase in frequency from initial resection (6.8%) to resection at recurrence (20%). The responder’s tumor at initial resection exhibited increased gene signatures of PD1low CD8+ T cells, chemokine signaling, and interferon gamma pathways. On PBMC phenotypic analysis, the responder demonstrated significantly higher percentages of CD137+ CD8+T cells (median 8.38% vs 3.24%, p=0.02) and lower percentages of Foxp3+CD137+ CD4+T cells compared to non-responders (median 18.5% vs. 38.5%, p=0.006). Interestingly, dynamic analysis of PBMCs showed that the responder demonstrated a lower percentage of PD1+ CD8+ T cells pre-immunotherapy (median 2.5% vs.12.4%, p=0.002), with persistent decrease over the course of treatment while non-responders showed no consistent pattern. CONCLUSION Our preliminary results demonstrate significant differences in tumor and peripheral blood immunogenomic characteristics between responder and non-responders to anti-LAG3 and anti-PD-1 therapy. These immunogenomic characteristics may help stratify patients’ response to combination ICIs.
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- 2019
32. Interleukin-36γ-producing macrophages drive IL-17-mediated fibrosis
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Patrick Cahan, Jennifer H. Elisseeff, Franck Housseau, Janis M. Taube, Drew M. Pardoll, David R. Maestas, Remi M. Schwab, Sven D. Sommerfeld, Ada Tam, Philippe Laffont, Christopher Cherry, Julie E. Stein, Sudipto Ganguly, and Liam Chung
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0301 basic medicine ,Phagocytosis ,Immunology ,Antigen presentation ,Population ,Mice, Transgenic ,02 engineering and technology ,Biology ,03 medical and health sciences ,Mice ,Immune system ,Fibrosis ,medicine ,Macrophage ,Animals ,education ,Mice, Knockout ,education.field_of_study ,Macrophages ,Interleukin-17 ,Interleukin ,General Medicine ,021001 nanoscience & nanotechnology ,medicine.disease ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Female ,Interleukin 17 ,0210 nano-technology ,Interleukin-1 - Abstract
Biomaterials induce an immune response and mobilization of macrophages, yet identification and phenotypic characterization of functional macrophage subsets in vivo remain limited. We performed single-cell RNA sequencing analysis on macrophages sorted from either a biologic matrix [urinary bladder matrix (UBM)] or synthetic biomaterial [polycaprolactone (PCL)]. Implantation of UBM promotes tissue repair through generation of a tissue environment characterized by a T helper 2 (TH2)/interleukin (IL)-4 immune profile, whereas PCL induces a standard foreign body response characterized by TH17/IL-17 and fibrosis. Unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle after UBM implantation. In the PCL tissue environment, we identified a CD9hi+IL-36γ+ macrophage subset that expressed TH17-associated molecules. These macrophages were virtually absent in mice lacking the IL-17 receptor, suggesting that they might be involved in IL-17-dependent immune and autoimmune responses. Identification and comparison of the unique phenotypical and functional macrophage subsets in mouse and human tissue samples suggest broad relevance of the new classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide targets for potential therapeutic modulation in tissue repair and pathology.
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- 2019
33. Mouse PVRIG Has CD8(+) T Cell–Specific Coinhibitory Functions and Dampens Antitumor Immunity
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Ofer Levy, Evgeny Tatirovsky, Xiaoyu Pan, Rupashree Sen, Liat Dassa, Sudipto Ganguly, Doron Levin, Meir Azulay, Zoya Alteber, Ran Salomon, Eran Ophir, Achinoam Ravet, Tal Fridman-kfir, Benjamin Murter, Arthur Machlenkin, Drew M. Pardoll, Ilan Vaknin, Ada Tam, and Yakir Vaknin
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0301 basic medicine ,Cancer Research ,Immunology ,Receptors, Cell Surface ,T-Cell Antigen Receptor Specificity ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Article ,B7-H1 Antigen ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Downregulation and upregulation ,Cell Line, Tumor ,Neoplasms ,Tumor Microenvironment ,Cytotoxic T cell ,Animals ,Humans ,Receptor ,Mice, Knockout ,Tumor microenvironment ,Chemistry ,Natural killer T cell ,Xenograft Model Antitumor Assays ,Tumor Burden ,Disease Models, Animal ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA Interference ,Poliovirus Receptor ,CD8 ,Biomarkers - Abstract
A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor–related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor–like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8+ T cells ex vivo. However, activated CD8+ T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8+ T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8+ T cells mounted a stronger antigen-specific effector response compared with wild-type CD8+ T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8+ T-cell effector function inhibited tumor growth in PVRIG−/− mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG−/− mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti–PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG–PVRL2 interactions results in increased CD8+ T-cell function and reduced tumor growth. See related article on p. 257
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- 2019
34. PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8(+) T-cell Function
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Abha Soni, Benjamin Murter, Ofer Levy, Kyle Hansen, Sarah Whelan, Ling Leung, Sudipto Ganguly, Spencer Liang, David Bernados, Mark A. White, Sandeep Kumar, Ilan Vaknin, Tian Li Wang, Ie Ming Shih, Janis M. Taube, Amanda Nickles Fader, Eran Ophir, Liat Dassa, Drew M. Pardoll, and Maya F. Kotturi
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0301 basic medicine ,Cancer Research ,CD96 ,medicine.medical_treatment ,Immunology ,Nectins ,Programmed Cell Death 1 Receptor ,Receptors, Cell Surface ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,TIGIT ,Neoplasms ,Medicine ,Cytotoxic T cell ,Animals ,Humans ,Receptors, Immunologic ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Blockade ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Cancer research ,business ,CD8 ,Protein Binding ,Signal Transduction - Abstract
Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8+ T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 was mediated by PVRIG and not TIGIT, demonstrating that the PVRIG–PVRL2 pathway is a nonredundant signaling node. A combination of PVRIG blockade with TIGIT or PD-1 blockade further increased T-cell activation. In human tumors, PVRIG expression on T cells was increased relative to normal tissue and trended with TIGIT and PD-1 expression. Tumor cells coexpressing PVR and PVRL2 were observed in multiple tumor types, with highest coexpression in endometrial cancers. Tumor cells expressing either PVR or PVRL2 were also present in numbers that varied with the cancer type, with ovarian cancers having the highest percentage of PVR−PVRL2+ tumor cells and colorectal cancers having the highest percentage of PVR+PVRL2− cells. To demonstrate a role of PVRIG and TIGIT on tumor-derived T cells, we examined the effect of PVRIG and TIGIT blockade on human tumor-infiltrating lymphocytes. For some donors, blockade of PVRIG increased T-cell function, an effect enhanced by combination with TIGIT or PD-1 blockade. In summary, we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG–PVRL2 and TIGIT–PVR pathways are nonredundant inhibitory signaling pathways. See related article on p. 244
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- 2019
35. Immunopathologic Stratification of Colorectal Cancer for Checkpoint Blockade Immunotherapy
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Qingfeng Zhu, Elizabeth D. Thompson, Laveet K. Aulakh, Teniola Oke, Cynthia L. Sears, Dung T. Le, Robert A. Anders, Anas H. Awan, Elizabeth M. Jaffee, Franck Housseau, Jennifer N. Durham, Drew M. Pardoll, Luis A. Diaz, Hao Wang, Bjarne Bartlett, Nicholas Siegel, Nicolas J. Llosa, and Brandon Luber
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Immunology ,Pembrolizumab ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,medicine ,Humans ,Neoplasm Metastasis ,Aged ,business.industry ,Mucin-1 ,Immunotherapy ,Middle Aged ,medicine.disease ,Primary tumor ,digestive system diseases ,Blockade ,Clinical trial ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Microsatellite Instability ,business ,Colorectal Neoplasms ,Checkpoint Blockade Immunotherapy ,Progressive disease - Abstract
Mismatch-repair deficiency in solid tumors predicts their response to PD-1 blockade. Based on this principle, pembrolizumab is approved as standard of care for patients with unresectable or metastatic microsatellite instability–high (MSI-H) cancer. Despite this success, a large majority of metastatic colorectal cancer patients are not MSI-H and do not benefit from checkpoint blockade treatment. Predictive biomarkers to develop personalized medicines and guide clinical trials are needed for these patients. We, therefore, asked whether immunohistologic stratification of metastatic colorectal cancer based on primary tumor PD-L1 expression associated with the presence or absence of extracellular mucin defines a subset of metastatic colorectal cancer patients who exhibit a preexisting antitumor immune response and who could potentially benefit from the checkpoint blockade. To address this, we studied 26 advanced metastatic colorectal cancer patients treated with pembrolizumab (NCT01876511). To stratify patients, incorporation of histopathologic characteristics (percentage of extracellular mucin) and PD-L1 expression at the invasive front were used to generate a composite score, the CPM (composite PD-L1 and mucin) score, which discriminated patients who exhibited clinical benefit (complete, partial, or stable disease) from those patients with progressive disease. When validated in larger cohorts, the CPM score in combination with MSI testing may guide immunotherapy interventions for colorectal cancer patient treatment.
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- 2019
36. Abstract PO008: The mouse colon modulates human microbes in transplantable murine tumor models after human fecal microbiota transfer (FMT)
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Cynthia L. Sears, Joell J. Gills, James R. White, Courtney Stevens, Drew M. Pardoll, Jarushka Naidoo, Fyza Y. Shaikh, and Fuad Mohammad
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Cancer Research ,medicine.medical_treatment ,Immunology ,Human microbiome ,Cancer ,Immunotherapy ,Biology ,medicine.disease ,biology.organism_classification ,Immune system ,Lymphatic system ,medicine ,Cancer research ,Microbiome ,Bacteria ,Feces - Abstract
While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers by producing durable anti-tumor responses, only 10-30% of treated patients respond to the available immunotherapy drugs and the ability to predict response to treatment remains elusive. Preliminary studies suggest that the gut microbiome may be an independent, novel modulator of systemic anti-tumor responses to ICIs, initially through bacterial interaction with the immune system in gut-associated lymphoid tissue. Multiple mouse tumor models have been developed to further elucidate the mechanism(s); specifically, FMT of human stool from ICI responder versus non-responder patients into germ-free mice suggests that responder human microbiota can facilitate tumor and immune responses in murine transplantable tumor models. However, data about how the mouse colon modulates the human microbiota are limited or lacking. We hypothesized that only a subset of specific human microbiota establish in the mouse colon and that analysis of these microbes may provide insight into the specific microbial communities that mediate ICI responses. To test this hypothesis, we first selected two human patients who were a distinct ICI responder (R) and nonresponder (NR) and tested their fecal samples in GF mice using syngeneic transplantable tumor models employing B16F0 and MC38 tumor cell lines. While the human ICI responses were replicated in these models, it was notable that individual mouse tumor responses were highly variable. To identify sources of experimental variability, we performed 16S rRNA amplicon sequencing on the human stool samples, experimental inocula, and mouse fecal samples at multiple time points. Our data show that the inocula (alpha diversity, composition) for each experiment were similar to the pre-treatment human stool. However, only 40-50% of human microbes were able to engraft in the mouse colon, and the relative abundance in the inocula was not the primary indicator for species engraftment. When we compared microbes across multiple experiments using beta diversity metrics, each experiment largely contained a distinct set of bacteria. Further analysis is underway to detect longitudinal microbiome shifts, cage effects, and/or bacteria enriched in small (responding) versus large (non-responding) tumors. Our results show that the mouse colon significantly modulates human microbiota in mouse FMT models and mouse microbiota analyses in germ-free models may yield mechanistic insights into bacteria facilitating ICI responses. Citation Format: Fyza Y. Shaikh, Joell J. Gills, James R. White, Fuad Mohammad, Courtney M. Stevens, Jarushka Naidoo, Drew M. Pardoll, Cynthia L. Sears. The mouse colon modulates human microbes in transplantable murine tumor models after human fecal microbiota transfer (FMT) [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO008.
- Published
- 2021
37. The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti–PD-1 Response in Patients with Renal Cell Carcinoma
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Charles G. Drake, Janis M. Taube, George J. Netto, Ludmila Danilova, Jinshui Fan, Robert A. Anders, Leslie Cope, Drew M. Pardoll, Haiying Xu, Theresa S. Pritchard, Tracee L. McMiller, Chris Cheadle, Alan E. Berger, Suzanne L. Topalian, and Maria Libera Ascierto
- Subjects
0301 basic medicine ,Cancer Research ,Leukocyte migration ,Combination therapy ,Programmed Cell Death 1 Receptor ,Immunology ,Biology ,Article ,B7-H1 Antigen ,Immunomodulation ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Renal cell carcinoma ,Cell Line, Tumor ,medicine ,Cluster Analysis ,Humans ,Glucuronosyltransferase ,Carcinoma, Renal Cell ,Melanoma ,Regulation of gene expression ,Gene Expression Profiling ,Immunity ,Cancer ,Prognosis ,medicine.disease ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Energy Metabolism ,Transcriptome ,Kidney cancer - Abstract
Pretreatment tumor PD-L1 expression has been shown to correlate with response to anti–PD-1/PD-L1 therapies. Yet, most patients with PD-L1+ tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD-1–targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD-L1. Formalin-fixed, paraffin-embedded pretreatment tumor biopsies expressing PD-L1 were derived from 13 RCC patients. RNA was isolated from PD-L1+ regions and subjected to whole genome microarray and multiplex quantitative (q)RT-PCR gene expression analysis. A balance between gene expression profiles reflecting metabolic pathways and immune functions was associated with clinical outcomes following anti–PD-1 therapy. In particular, the expression of genes involved in metabolic and solute transport functions such as UGT1A family members, also found in kidney cancer cell lines, was associated with treatment failure in patients with PD-L1+ RCC. Conversely, tumors from responding patients overexpressed immune markers such as BACH2, a regulator of CD4+ T-cell differentiation, and CCL3 involved in leukocyte migration. These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti–PD-1. Cancer Immunol Res; 4(9); 726–33. ©2016 AACR. See related Spotlight by Ohashi, p. 719.
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- 2016
38. MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor
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Lewis Novack, Ren-Chin Wu, Ying Zheng, Jinhui Tao, Joseph Barbi, Fan Pan, Paolo D. A. Vignali, Chao Yi Wu, Shashika Bandara, Huang-Yu Yang, Chih-Wei Yang, Kwang Yu Chang, Xuhao Ni, Huabin Li, Drew M. Pardoll, Junran Zhang, Xiaoping Yang, Benjamin V. Park, and Xingmei Wu
- Subjects
0301 basic medicine ,Regulatory T cell ,medicine.medical_treatment ,Immunology ,Nerve Tissue Proteins ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Article ,Mice ,03 medical and health sciences ,RNA interference ,microRNA ,medicine ,Animals ,Humans ,Immunology and Allergy ,Transcription factor ,Cells, Cultured ,Mice, Knockout ,Interleukin-6 ,Effector ,Interleukin-2 Receptor alpha Subunit ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,Colitis ,Cell biology ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Disease Models, Animal ,MicroRNAs ,Self Tolerance ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Cytokine ,Ectopic expression ,Carrier Proteins - Abstract
Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos. Treg cell suppressive activity was diminished upon overexpression of miR-17 in vitro and in vivo, which was mitigated upon co-expression of an Eos mutant lacking miR-17 target sites. Also, RNAi of miR-17 resulted in enhanced suppressive activity. Ectopic expression of miR-17 imparted effector-T-cell-like characteristics to Treg cells via the de-repression of genes encoding effector cytokines. Thus, miR-17 provides a potent layer of Treg cell control through targeting Eos and additional Foxp3 co-regulators.
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- 2016
39. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
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Robert A. Anders, Janis M. Taube, Drew M. Pardoll, and Suzanne L. Topalian
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0301 basic medicine ,Cell cycle checkpoint ,General Mathematics ,medicine.medical_treatment ,Biology ,Bioinformatics ,Article ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,CTLA-4 Antigen ,Lung cancer ,Mechanism (biology) ,Applied Mathematics ,Cell Cycle Checkpoints ,medicine.disease ,Immune checkpoint ,Blockade ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Biomarker (medicine) - Abstract
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
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- 2016
40. Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination
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Charles G. Drake, Michael Lim, Peter Lauer, Emily G. Baxi, Christopher J. Nirschl, Jacob Ruzevick, Dirk G. Brockstedt, Christopher M. Jackson, Christina M. Kochel, Nicholas M. Durham, Henry Brem, Peter A. Calabresi, Andrew Daniels, Angela Alme, Janis M. Taube, Thomas W. Dubensky, Carlos A. Pardo, Brian Francica, Jimmy Elias, and Drew M. Pardoll
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Melanoma, Experimental ,CD8-Positive T-Lymphocytes ,Article ,Immune tolerance ,Central Nervous System Neoplasms ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Antigens, Neoplasm ,Transforming Growth Factor beta ,Immune Tolerance ,Animals ,Humans ,Medicine ,Cytotoxic T cell ,Brain Neoplasms ,business.industry ,Melanoma ,Vaccination ,Cancer ,medicine.disease ,Radiation therapy ,030104 developmental biology ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Female ,Microglia ,business ,T-Lymphocytes, Cytotoxic - Abstract
Purpose: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental Design: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor–bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. Results: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen–specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia. Conclusions: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials. Clin Cancer Res; 22(5); 1161–72. ©2015 AACR.
- Published
- 2016
41. Abstract A32: Characterizing patterns of cytokine coexpression with immune checkpoint markers in CD4 and CD8 tumor-infiltrating lymphocytes
- Author
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Chetan Bettegowda, Jon D. Weingart, Christopher M. Jackson, Denis Routkevitch, Ballentine Carter, Charles G. Drake, Trinity J. Bivalacqua, Ashley E. Ross, Alyza M. Skaist, Ayush Pant, Christina Jackson, Laura Saleh, Mohamad E. Allaf, Christina M. Kochel, Michael Lim, Linda A. Snyder, Angelo M. DeMarzo, Anuj Gupta, Luigi Marchionni, Wikum Dinalankara, John Choi, Drew M. Pardoll, Edward M. Schaeffer, Thomas R. Nirschl, and Henry Brem
- Subjects
Cancer Research ,Cytokine ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,Immunology ,Cancer research ,medicine ,Biology ,Immune checkpoint ,CD8 - Abstract
In recent years, immunotherapy has become one of the most exciting and promising avenues to cancer treatment. Treatment with immune checkpoint inhibitors has managed to produce long-term remission of solid tumors in many patients. However, patients who respond well to such treatment are often a minority; this is particularly the case with some cancers such as renal cell carcinoma, non-small cell lung cancer, and glioblastoma, where many patients either derive no benefit or only a short-term benefit. In this analysis, we examined gene expression data from RNA sequencing experiments that compared tumor-infiltrating lymphocytes (TIL) with paired circulating lymphocytes from patients with renal cell carcinoma (RCC), bladder cancer (BLCA), prostate cancer (PRAD), and glioblastoma (GBM). Our analysis helped to characterize global CD4 and CD8 TIL gene expression patterns among these four cohorts. Further, using the expression profiles for known immune checkpoint markers PD-1, TIM-3, and LAG-3 in CD8 cells, we dichotomized the patient samples into potential checkpoint inhibitor responder and nonresponder groups. This model was then used to identify other genes that are associated with CD8 TIL exhaustion, which may lead to the identification of cytokines useful in discovering specific therapeutic targets. Citation Format: Christopher M. Jackson, Wikum Dinalankara, John Choi, Thomas R. Nirschl, Christina M. Kochel, Ayush Pant, Denis Routkevitch, Laura Saleh, Christina Jackson, Alyza M. Skaist, Anuj Gupta, Linda A. Snyder, Edward M. Schaeffer, Ashley E. Ross, Ballentine Carter, Mohamad E. Allaf, Trinity J. Bivalacqua, Angelo M. DeMarzo, Jon D. Weingart, Chetan Bettegowda, Henry Brem, Drew M. Pardoll, Luigi Marchionni, Charles G. Drake, Michael Lim. Characterizing patterns of cytokine coexpression with immune checkpoint markers in CD4 and CD8 tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A32.
- Published
- 2020
42. The Mutation-Associated Neoantigen Functional Expansion of Specific T cells (MANAFEST) assay: a sensitive platform for monitoring antitumor immunity
- Author
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Hok Yee Chan, Jiajia Zhang, Kellie N. Smith, Victor E. Velculescu, Prerna Suri, Franck Housseau, Patrick M. Forde, Leslie Cope, Margueritta El Asmar, Ada Tam, Kristen A. Marrone, Alexander S. Baras, John-William Sidhom, Julie R. Brahmer, Ludmila Danilova, Drew M. Pardoll, Haidan Guo, Valsamo Anagnostou, Justina X. Caushi, and Jarushka Naidoo
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,T cell ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Article ,03 medical and health sciences ,Epitopes ,0302 clinical medicine ,Antigen ,Immunity ,Antigens, Neoplasm ,Monitoring, Immunologic ,Carcinoma, Non-Small-Cell Lung ,Neoplasms ,medicine ,Humans ,Cells, Cultured ,Immunity, Cellular ,ELISPOT ,T-cell receptor ,Computational Biology ,Immunotherapy ,In vitro ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer research - Abstract
Mutation-associated neoantigens (MANA) are a target of antitumor T-cell immunity. Sensitive, simple, and standardized assays are needed to assess the repertoire of functional MANA-specific T cells in oncology. Assays analyzing in vitro cytokine production such as ELISpot and intracellular cytokine staining have been useful but have limited sensitivity in assessing tumor-specific T-cell responses and do not analyze antigen-specific T-cell repertoires. The FEST (Functional Expansion of Specific T cells) assay described herein integrates T-cell receptor sequencing of short-term, peptide-stimulated cultures with a bioinformatic platform to identify antigen-specific clonotypic amplifications. This assay can be adapted for all types of antigens, including MANAs via tumor exome-guided prediction of MANAs. Following in vitro identification by the MANAFEST assay, the MANA-specific CDR3 sequence can be used as a molecular barcode to detect and monitor the dynamics of these clonotypes in blood, tumor, and normal tissue of patients receiving immunotherapy. MANAFEST is compatible with high-throughput routine clinical and lab practices. Cancer Immunol Res; 6(8); 888–99. ©2018 AACR.
- Published
- 2018
43. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM
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Su Myeong Park, Chul-Kee Park, Michael Lim, Tomas Garzon-Muvdi, Andrew S. Luksik, Henry Brem, Mark J. Selby, Betty Tyler, Tamrin Chowdhury, Alan J. Korman, Eileen Kim, Debebe Theodros, Dimitrios Mathios, Alice L. Hung, Xiaobu Ye, Russell Maxwell, Yuanxuan Xia, Zineb Belcaid, Drew M. Pardoll, Christopher M. Jackson, Adela Wu, Je In Youn, and Bryan C. Barnhart
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Myeloid ,TIGIT ,dendritic cell ,T cell ,medicine.medical_treatment ,Immunology ,PVR ,lcsh:RC254-282 ,GBM ,03 medical and health sciences ,Immune system ,Glioma ,glioma ,PD-1 ,medicine ,Immunology and Allergy ,CD155 ,Original Research ,business.industry ,Dendritic cell ,Immunotherapy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,checkpoint inhibitor ,Oncology ,Cancer research ,immunotherapy ,business ,lcsh:RC581-607 ,CD8 - Abstract
The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.
- Published
- 2018
44. Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system
- Author
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Christopher M. Jackson, Zineb Belcaid, Eileen S. Kim, John Choi, Tomas Garzon-Muvdi, Xiaobu Ye, Phuoc T. Tran, Dimitrios Mathios, Alice L. Hung, Henry Brem, Lawrence Kleinberg, Yuanxuan Xia, Michael Lim, Russell Maxwell, Adela Wu, Drew M. Pardoll, Noah Gorelick, Debebe Theodros, Andrew S. Luksik, and Kristin J. Redmond
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,corticosteroid ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Central nervous system ,Brain tumor ,dexamethasone ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Glioma ,Internal medicine ,glioma ,PD-1 ,medicine ,Immunology and Allergy ,Original Research ,business.industry ,Immunosuppression ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,central nervous system ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,colon adenocarcinoma ,030220 oncology & carcinogenesis ,Corticosteroid ,immunotherapy ,lcsh:RC581-607 ,business ,brain tumor - Abstract
Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.
- Published
- 2018
45. Caspase-1 from Human Myeloid Derived Suppressor Cells Can Promote T cell–Independent Tumor Proliferation
- Author
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Michael J. Korrer, Peter J. Murray, Young J. Kim, David L. Masica, Qi Zeng, Mikhail Gorbounov, Juan Fu, and Drew M. Pardoll
- Subjects
0301 basic medicine ,Cancer Research ,Adoptive cell transfer ,T cell ,T-Lymphocytes ,Immunology ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neoplasms ,medicine ,Animals ,Humans ,Cells, Cultured ,Cell Proliferation ,Mice, Knockout ,Cell growth ,Myeloid-Derived Suppressor Cells ,Caspase 1 ,Adoptive Transfer ,Squamous carcinoma ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid-derived Suppressor Cell ,Bone marrow ,Carcinogenesis - Abstract
Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell–independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/– MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1–dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo, growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell–depleted conditions. Adoptive transfer of wild-type Gr-1+CD11b+ MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor-intrinsic MyD88-dependent carcinogenesis. In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell–independent mediator of tumor proliferation. Cancer Immunol Res; 6(5); 566–77. ©2018 AACR.
- Published
- 2018
46. Nanoparticulate matter exposure results in neuroinflammatory changes in the corpus callosum
- Author
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Qinghai Liu, William J. Mack, Kristina Shkirkova, Arati Patel, Hank Cheng, Drew M Hodis, Todd E. Morgan, Caleb E. Finch, Constantinos Sioutas, Krista Lamorie-Foote, Michelle Connor, and Robin Babadjouni
- Subjects
Central Nervous System ,0301 basic medicine ,Physiology ,Complement System ,Complement receptor ,Corpus callosum ,medicine.disease_cause ,Nervous System ,Biochemistry ,Immune Receptors ,C5a receptor ,Corpus Callosum ,Mice ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Materials ,Staining ,Complement component 5 ,Immune System Proteins ,Multidisciplinary ,Microglia ,integumentary system ,Complement C5 ,Brain ,Complement Receptors ,Pollution ,Specimen preparation and treatment ,Particulates ,medicine.anatomical_structure ,Physical Sciences ,Medicine ,Anatomy ,Cellular Types ,Research Article ,Signal Transduction ,medicine.medical_specialty ,Science ,Immunology ,Materials Science ,Neurocognitive Disorders ,Glial Cells ,Biology ,White matter ,03 medical and health sciences ,Air Pollution ,Internal medicine ,medicine ,Animals ,Humans ,Microglial Cells ,Neuroinflammation ,Inflammation ,Ecology and Environmental Sciences ,DAPI staining ,Biology and Life Sciences ,Proteins ,Cell Biology ,Research and analysis methods ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,13. Climate action ,Immune System ,Mixtures ,Nuclear staining ,Nanoparticles ,Particulate Matter ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Epidemiological studies have established an association between air pollution particulate matter exposure (PM2.5) and neurocognitive decline. Experimental data suggest that microglia play an essential role in air pollution PM-induced neuroinflammation and oxidative stress. This study examined the effect of nano-sized particulate matter (nPM) on complement C5 deposition and microglial activation in the corpus callosum of mice (C57BL/6J males). nPM was collected in an urban Los Angeles region impacted by traffic emissions. Mice were exposed to 10 weeks of re-aerosolized nPM or filtered air for a cumulative 150 hours. nPM-exposed mice exhibited reactive microglia and 2-fold increased local deposition of complement C5/ C5α proteins and complement component C5a receptor 1 (CD88) in the corpus callosum. However, serum C5 levels did not differ between nPM and filtered air cohorts. These findings demonstrate white matter C5 deposition and microglial activation secondary to nPM exposure. The C5 upregulation appears to be localized to the brain.
- Published
- 2018
47. Correction to: persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
- Author
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Qingfeng Zhu, Victor E. Velculescu, Bjarne Bartlett, Haidan Guo, Robert A. Anders, Drew M. Pardoll, Luis A. Diaz, William H. Sharfman, Brandon Luber, Prerna Suri, Nicholas Siegel, Valsamo Anagnostou, Sune Justesen, Patrick M. Forde, Hok Yee Chan, John-William Sidhom, Hao Wang, Franco Verde, Nickolas Papadopoulos, Dung T. Le, Teniola Oke, Bert Vogelstein, Elizabeth D. Thompson, Cynthia L. Sears, Hongni Fan, Tricia R. Cottrell, Kristen A. Marrone, Leslie Cope, Ada J. Tam, Ludmila Danilova, Anas H. Awan, Julie R. Brahmer, Jennifer N. Durham, Joanne Riemer, Jarushka Naidoo, Nicolas J. Llosa, Kenneth W. Kinzler, Janis M. Taube, Franck Housseau, Laveet K. Aulakh, and Kellie N. Smith
- Subjects
Pharmacology ,Cancer Research ,Oncogene ,business.industry ,Immunology ,Mutant ,Anti pd 1 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Oncology ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Medicine ,business - Published
- 2019
48. Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis
- Author
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Jaime L. Wolfe, Cynthia L. Sears, Shaoguang Wu, David L. Huso, Xinqun Wu, Drew M. Pardoll, Abby L. Geis, Hongni Fan, and Franck Housseau
- Subjects
Interleukin 2 ,Regulatory T cell ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Inflammation ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Lymphocyte Depletion ,Bacteroides fragilis ,Mice ,Immune system ,Intestinal mucosa ,T-Lymphocyte Subsets ,medicine ,Animals ,Intestinal Mucosa ,Colitis ,Interleukin-17 ,hemic and immune systems ,Bacteroides Infections ,medicine.disease ,Disease Models, Animal ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Colonic Neoplasms ,Immunology ,Interleukin-2 ,Th17 Cells ,Interleukin 17 ,medicine.symptom ,Carcinogenesis ,medicine.drug - Abstract
Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune-suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote enterotoxigenic Bacteroides fragilis (ETBF). Depletion of Tregs in ETBF-colonized C57BL/6 FOXP3DTR mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL17 to IFNγ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL17 inflammation and was independent of IFNγ. Treg enhancement of IL17 production is cell-extrinsic. IL2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL2 in the local microenvironment, allowing the Th17 development necessary to promote ETBF-triggered neoplasia, and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis. Significance: Tregs promote an oncogenic immune response to a common human symbiote associated with inflammatory bowel disease and colorectal cancer. Our data define mechanisms by which mucosal Tregs, despite suppressing excessive inflammation, promote the earliest stages of immune procarcinogenesis via enhancement of IL17 production at the expense of IFNγ production. Cancer Discov; 5(10); 1098–109. ©2015 AACR. See related commentary by Irrazabal and Martin, p. 1021. This article is highlighted in the In This Issue feature, p. 1005
- Published
- 2015
49. Cancer and the Immune System: Basic Concepts and Targets for Intervention
- Author
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Drew M. Pardoll
- Subjects
business.industry ,medicine.medical_treatment ,Cancer ,Hematology ,Immunotherapy ,medicine.disease ,Cancer Vaccines ,Article ,Immune tolerance ,Vaccination ,Immune system ,Oncology ,Antigen ,Immune System ,Neoplasms ,Intervention (counseling) ,Immunology ,Immune Tolerance ,Animals ,Humans ,Medicine ,business ,Cancer immunology - Abstract
A number of consensuses regarding cancer immunology have recently emerged from both preclinical immunotherapy models and analysis of cancer patients. First and foremost, the natural state of endogenous tumor reactive T cells is characterized by general hyporesponsiveness or anergy. This is likely due to a number of mechanisms that tumors use to induce tolerance as they develop. While many of the newer generation vaccines can effectively transfer antigen to and activate dendritic cells, T-cell tolerance remains a major barrier that is difficult to overcome by vaccination alone. Preclinical models demonstrate that for poorly immunogenic tumors, once tolerance has been established, therapeutic vaccines alone are ineffective at curing animals with a significant established tumor burden. However, combination strategies of vaccination together with inhibitors of immunologic checkpoints and agonists for co-stimulatory pathways are proving capable of overcoming tolerance and generating significant anti-tumor responses even in cases of established metastatic cancer.
- Published
- 2015
50. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model
- Author
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Dimitrios Mathios, Warren D. Marcus, Hing C. Wong, Chul-Kee Park, Michael Lim, Drew M. Pardoll, Peter R. Rhode, Sarah Alter, and Emily K. Jeng
- Subjects
0301 basic medicine ,Cancer Research ,Tumor microenvironment ,biology ,business.industry ,medicine.medical_treatment ,Immunotherapy ,Malignancy ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Cytokine ,Oncology ,Interleukin 15 ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Cancer research ,biology.protein ,Antibody ,business ,CD8 - Abstract
Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.
- Published
- 2015
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