43 results on '"Freeman, Gordon J."'
Search Results
2. Abstract 62: Development of dual-targeted fine-tuned immune restoring (DFIR) CAR T cell therapy for clear cell renal cell carcinoma (ccRCC)
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Wang, Yufei, primary, Buck, Alicia, additional, Grimaud, Marion, additional, Kodangattil, Sreekumar, additional, Razimbaud, Cecile, additional, Fayed, Atef, additional, Chang, Matthew, additional, Culhane, Aedin, additional, Braun, David A., additional, Choueiri, Toni K., additional, Wu, Catherine J., additional, Wei, Kevin S., additional, Chan, Leo L., additional, Piel, Brandon P., additional, Ivanova, Elena V., additional, Paweletz, Cloud P., additional, Barbie, David A., additional, Jennings, Rebecca, additional, Ficial, Miriam, additional, Sticco-Ivins, Maura Aliezah, additional, Signoretti, Sabina, additional, Freeman, Gordon J., additional, Zhu, Quan K., additional, and Marasco, Wayne A., additional
- Published
- 2021
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3. Abstract PR9: Loss of PD-1 promotes antitumor immunity by improving functions of both PD-1+ and PD-1- CD8+ T cells in the tumor microenvironment
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Pauken, Kristen E., primary, Juneja, Vikram R., additional, Ringel, Alison, additional, Rowe, Jared H., additional, Burke, Kelly P., additional, Sage, Peter T., additional, LaFleur, Martin W., additional, Kuchroo, Juhi R., additional, Ron-Harel, Noga, additional, Maleri, Seth, additional, Long, Jaclyn M., additional, Freeman, Gordon J., additional, Chevrier, Nicolas, additional, Haigis, Marcia C., additional, and Sharpe, Arlene H., additional
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- 2020
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4. Abstract 3779: Clonal tracing reveals different mechanisms of resistance to immune checkpoint blockade
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Gu, Shengqing, primary, Hu, Xihao, additional, Wang, Xiaoqing, additional, Jiang, Peng, additional, Li, Ziyi, additional, Traugh, Nicole, additional, Bu, Xia, additional, Xing, Xiaofang, additional, Freeman, Gordon J., additional, Brown, Myles, additional, and Liu, Xiaole S., additional
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- 2019
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5. Abstract B077: Signatures of T-cell dysfunction and exclusion predict cancer immunotherapy response
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Jiang, Peng, primary, Gu, Shengqing, additional, Pan, Deng, additional, Fu, Jingxin, additional, Sahu, Avinash, additional, Hu, Xihao, additional, Li, Ziyi, additional, Traugh, Nicole, additional, Bu, Xia, additional, Li, Bo, additional, Liu, Jun, additional, Freeman, Gordon J, additional, Brown, Myles A, additional, Wucherpfennig, Kai W., additional, and Liu, Xiaole Shirley, additional
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- 2019
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6. Abstract A19: PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor
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Pauken, Kristen E., primary, Juneja, Vikram R., additional, Sage, Peter T., additional, LaFleur, Martin W., additional, Kuchroo, Juhi R., additional, Ringel, Alison, additional, Ron-Harel, Noga, additional, Maleri, Seth P., additional, Freeman, Gordon J., additional, Chevrier, Nicolas, additional, Haigis, Marcia C., additional, and Sharpe, Arlene H., additional
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- 2018
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7. Abstract A21: Characterization of the immune environment in the in situ to invasive breast carcinoma transition
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Alcazar, Carlos R. Gil del, primary, Huh, SungJin, additional, Ekram, Muhammad B., additional, Trinh, Anne, additional, Liu, Lin L., additional, Beca, Francisco, additional, Xiaoyuan, Zi, additional, Kwak, Misuk, additional, Bergholtz, Helga, additional, Su, Ying, additional, Ding, Lina, additional, Russnes, Hege G., additional, Richardson, Andrea L., additional, Babski, Kirsten, additional, Kim, Elizabeth Min Hui, additional, McDonnell, Charles H., additional, Wagner, Jon, additional, Rowberry, Ron, additional, Freeman, Gordon J., additional, Dillon, Deborah, additional, Sorlie, Therese, additional, Coussens, Lisa M., additional, Garber, Judy E., additional, Fan, Rong, additional, Bobolis, Kristie, additional, Allred, D. Craig, additional, Jeong, Joon, additional, Park, So Yeon, additional, Michor, Franziska, additional, and Polyak, Kornelia, additional
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- 2018
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8. Abstract 417: Defining molecular mechanisms of resistance to glioblastoma immunity using a novel CRISPR/Cas9in vivoloss-of-function screening platform
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Neagu, Martha R., primary, Manguso, Robert T., additional, Pope, Hans, additional, Speranza, Maria C., additional, Freeman, Gordon J., additional, Doench, John, additional, Sharpe, Arlene H., additional, and Haining, William Nicholas, additional
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- 2017
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9. Abstract A075: Preclinical analysis of combinatorial glioblastoma therapy with the prodrug-mediated gene therapy vector AdV-TK and immune checkpoint inhibition in GBM therapy
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Speranza, Maria Carmela, primary, Kasai, Kazue, additional, Ricklefs, Franz, additional, Klein, Sarah R., additional, Passaro, Carmela, additional, Nakashima, Hiroshi, additional, Kaufmann, Johanna, additional, Bronisz, Agnieszka, additional, Aguilar-Cordova, Estuardo, additional, Guzik, Brian W., additional, Freeman, Gordon J., additional, Reardon, David A., additional, Wen, Patrick, additional, Chiocca, E. Antonio, additional, and Lawler, Sean E., additional
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- 2016
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10. Abstract CT133: Association of programmed death-ligand 1 (PD-L1) and 2 (PD-L2) expression with nivolumab (NIVO) efficacy in advanced melanoma (MEL)
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Rodig, Scott J., primary, Gjini, Evisa, additional, Desai, Kaushal, additional, Jin, Chelsea, additional, Horak, Christine, additional, Ruisi, Mary, additional, Weber, Jeffrey, additional, Freeman, Gordon J., additional, and Hodi, F. Stephen, additional
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- 2016
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11. Abstract 4184: Pre-clinical study using KRAS mutant mouse models for lung cancer immunotherapy together with MEK inhibition
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Deng, Jiehui, primary, Li, Shuai, additional, Herter-Sprie, Grit, additional, Smith, Paul D., additional, Freeman, Gordon J., additional, Engelman, Jeffrey A., additional, Hammerman, Peter, additional, and Wong, Kwok-Kin, additional
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- 2016
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12. Abstract 4359: Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent
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Kamphorst, Alice O., primary, Wieland, Andreas, additional, Yang, Shu, additional, Nasti, Tahseen, additional, Zhang, Ruan, additional, Barber, Daniel L., additional, Konieczny, Bogumila T., additional, Koenig, Lydia, additional, Yu, Ke, additional, Sica, Gabriel, additional, Owonikoko, Taofeek K., additional, Pillai, Rathi, additional, Ramalingam, Suresh S., additional, Sharpe, Arlene H., additional, Freeman, Gordon J., additional, Turka, Laurence A., additional, Araki, Koichi, additional, and Ahmed, Rafi, additional
- Published
- 2016
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13. Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors--Response.
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Duraiswamy, Jaikumar, Freeman, Gordon J., and Coukos, George
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CANCER vaccines ,TUMOR genetics - Abstract
A response by Jaikumar Duraiswamy et al. to a letter to the editor about their article "Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors" in the 2013 issue is presented.
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- 2014
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14. Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors.
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Duraiswamy, Jaikumar, Kaluza, Karen M., Freeman, Gordon J., and Coukos, George
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CD81 antigen , *T cells , *APOPTOSIS , *CYTOTOXIC T cells , *LYMPHOCYTES , *TUMORS , *CYTOKINES , *CELLULAR signal transduction - Abstract
Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation ofCD8+ Tcells andFoxp3+ Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8+ T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8+ tumor-infiltrating lymphocytes (TIL) expressedPD-1,whereas one third to half ofCD8+ TIL coexpressedPD-1 and CTLA-4. Double-positive (PD-1+CTLA-4+) CD8+ TIL had characteristics of more severe dysfunction than single-positive (PD-1+ or CTLA-4+) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector Tcells and maintaining tumor Tregs, and that PD-1/PDL1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression. [ABSTRACT FROM AUTHOR]
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- 2013
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15. Age-associated contraction of tumor-specific T cells impairs antitumor immunity.
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Georgiev P, Han S, Huang AY, Nguyen TH, Drijvers JM, Creasey H, Pereira JA, Yao CH, Park JS, Conway TS, Fung ME, Liang D, Peluso M, Joshi S, Rowe JH, Miller BC, Freeman GJ, Sharpe AH, Haigis MC, and Ringel AE
- Abstract
Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in antitumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We found that multiple syngeneic cancers grew more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T-cell responses. By systematically mapping immune cell profiles within tumors, we identified loss of tumor antigen-specific CD8+ T cells as a primary feature accelerating the growth of tumors in aged mice and driving resistance to immunotherapy. When antigen-specific T cells from young adult mice were administered to aged mice, tumor outgrowth was delayed and the aged animals became sensitive to PD-1 blockade. These studies reveal how age-associated CD8+ T-cell dysfunction may license tumorigenesis in elderly patients and have important implications for the use of aged mice as pre-clinical models of aging and cancer.
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- 2024
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16. Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade.
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Rowe JH, Elia I, Shahid O, Gaudiano EF, Sifnugel NE, Johnson S, Reynolds AG, Fung ME, Joshi S, LaFleur MW, Park JS, Pauken KE, Rabinowitz JD, Freeman GJ, Haigis MC, and Sharpe AH
- Subjects
- Humans, CD8-Positive T-Lymphocytes metabolism, Formates, Dietary Supplements, Tumor Microenvironment, Programmed Cell Death 1 Receptor metabolism, Neoplasms genetics
- Abstract
The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function., Significance: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti-PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell-mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489., (©2023 American Association for Cancer Research.)
- Published
- 2023
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17. Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer.
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Gil Del Alcazar CR, Trinh A, Alečković M, Rojas Jimenez E, Harper NW, Oliphant MUJ, Xie S, Krop ED, Lulseged B, Murphy KC, Keenan TE, Van Allen EM, Tolaney SM, Freeman GJ, Dillon DA, Muthuswamy SK, and Polyak K
- Subjects
- Animals, Female, Hormones, Humans, Immunologic Factors, Immunotherapy, Mice, Rats, Rats, Sprague-Dawley, Receptors, Antigen, T-Cell, Breast Neoplasms genetics, Breast Neoplasms immunology, Breast Neoplasms therapy
- Abstract
Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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18. Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses.
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Bu X, Juneja VR, Reynolds CG, Mahoney KM, Bu MT, McGuire KA, Maleri S, Hua P, Zhu B, Klein SR, Greenfield EA, Armand P, Ritz J, Sharpe AH, and Freeman GJ
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- Animals, Antibodies, Monoclonal pharmacology, Cell Line, Tumor, Humans, Mice, Phosphorylation, Signal Transduction, Antibodies, Monoclonal therapeutic use, Immunity immunology, Immunotherapy methods, Programmed Cell Death 1 Receptor therapeutic use
- Abstract
PD-1 expression marks activated T cells susceptible to PD-1-mediated inhibition but not whether a PD-1-mediated signal is being delivered. Molecular predictors of response to PD-1 immune checkpoint blockade (ICB) are needed. We describe a monoclonal antibody (mAb) that detects PD-1 signaling through the detection of phosphorylation of the immunotyrosine switch motif (ITSM) in the intracellular tail of mouse and human PD-1 (phospho-PD-1). We showed PD-1
+ tumor-infiltrating lymphocytes (TILs) in MC38 murine tumors had high phosphorylated PD-1, particularly in PD-1+ TIM-3+ TILs. Upon PD-1 blockade, PD-1 phosphorylation was decreased in CD8+ TILs. Phospho-PD-1 increased in T cells from healthy human donors after PD-1 engagement and decreased in patients with Hodgkin lymphoma following ICB. These data demonstrate that phosphorylation of the ITSM motif of PD-1 marks dysfunctional T cells that may be rescued with PD-1 blockade. Detection of phospho-PD-1 in TILs is a potential biomarker for PD-1 immunotherapy responses., (©2021 The Authors; Published by the American Association for Cancer Research.)- Published
- 2021
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19. Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade.
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Gu SS, Zhang W, Wang X, Jiang P, Traugh N, Li Z, Meyer C, Stewig B, Xie Y, Bu X, Manos MP, Font-Tello A, Gjini E, Lako A, Lim K, Conway J, Tewari AK, Zeng Z, Sahu AD, Tokheim C, Weirather JL, Fu J, Zhang Y, Kroger B, Liang JH, Cejas P, Freeman GJ, Rodig S, Long HW, Gewurz BE, Hodi FS, Brown M, and Liu XS
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- B7-H1 Antigen metabolism, Data Mining, Gene Expression Profiling, Histocompatibility Antigens Class I metabolism, Humans, Immune Checkpoint Inhibitors pharmacology, Immunotherapy, Tumor Microenvironment drug effects, Immune Checkpoint Inhibitors therapeutic use, Neoplasms drug therapy
- Abstract
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3 -knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. SIGNIFICANCE: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell-based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials. This article is highlighted in the In This Issue feature, p. 1307 ., (©2021 American Association for Cancer Research.)
- Published
- 2021
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20. KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1.
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Bhatt RS, Berjis A, Konge JC, Mahoney KM, Klee AN, Freeman SS, Chen CH, Jegede OA, Catalano PJ, Pignon JC, Sticco-Ivins M, Zhu B, Hua P, Soden J, Zhu J, McDermott DF, Arulanandam AR, Signoretti S, and Freeman GJ
- Subjects
- Animals, B7-H1 Antigen immunology, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Cell Line, Tumor, Humans, Immunoglobulins immunology, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Killer Cells, Natural immunology, Mice, Mice, Inbred BALB C, Receptors, KIR immunology, T-Lymphocytes immunology, B7-H1 Antigen metabolism, Carcinoma, Renal Cell immunology, Immunoglobulins metabolism, Kidney Neoplasms immunology, Receptors, KIR metabolism
- Abstract
Blockade of the PD1 pathway is a broadly effective cancer therapy, but additional immune-inhibitory pathways contribute to tumor immune evasion. HERV-H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7) is a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2). However, HHLA2 has also been known to have inhibitory effects on T cells. Here, we report that we have identified killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells and have generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. It is known that HHLA2 is frequently expressed in several tumor types, including clear cell renal cell carcinoma (ccRCC). We found that HHLA2 expression was nonoverlapping with PDL1 expression in ccRCC, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PDL1. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion. See related Spotlight on p. 128 ., (©2020 American Association for Cancer Research.)
- Published
- 2021
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21. Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade.
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Gstalder C, Liu D, Miao D, Lutterbach B, DeVine AL, Lin C, Shettigar M, Pancholi P, Buchbinder EI, Carter SL, Manos MP, Rojas-Rudilla V, Brennick R, Gjini E, Chen PH, Lako A, Rodig S, Yoon CH, Freeman GJ, Barbie DA, Hodi FS, Miles W, Van Allen EM, and Haq R
- Subjects
- Aged, Animals, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Cell Line, Tumor transplantation, DEAD Box Protein 58 genetics, DEAD Box Protein 58 metabolism, Disease Models, Animal, F-Box-WD Repeat-Containing Protein 7 metabolism, Gene Expression Regulation, Neoplastic immunology, HeLa Cells, Humans, Immune Checkpoint Inhibitors therapeutic use, Interferon-Induced Helicase, IFIH1 genetics, Interferon-Induced Helicase, IFIH1 metabolism, Loss of Function Mutation, Male, Mice, Mutagenesis, Site-Directed, Programmed Cell Death 1 Receptor antagonists & inhibitors, RNA, Double-Stranded immunology, RNA, Double-Stranded metabolism, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Skin Neoplasms genetics, Skin Neoplasms immunology, Skin Neoplasms pathology, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Drug Resistance, Neoplasm genetics, F-Box-WD Repeat-Containing Protein 7 genetics, Immune Checkpoint Inhibitors pharmacology, Skin Neoplasms drug therapy
- Abstract
The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7 , whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7 -deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations. This article is highlighted in the In This Issue feature, p. 1241 ., (©2020 American Association for Cancer Research.)
- Published
- 2020
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22. In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras -Mutant Lung Adenocarcinoma.
- Author
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Li F, Huang Q, Luster TA, Hu H, Zhang H, Ng WL, Khodadadi-Jamayran A, Wang W, Chen T, Deng J, Ranieri M, Fang Z, Pyon V, Dowling CM, Bagdatlioglu E, Almonte C, Labbe K, Silver H, Rabin AR, Jani K, Tsirigos A, Papagiannakopoulos T, Hammerman PS, Velcheti V, Freeman GJ, Qi J, Miller G, and Wong KK
- Subjects
- Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung pathology, Animals, CRISPR-Cas Systems genetics, Cell Cycle Proteins genetics, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Line, Tumor, Disease Models, Animal, Epigenesis, Genetic immunology, Gene Expression Regulation, Neoplastic immunology, Gene Knockout Techniques, HEK293 Cells, Humans, Immune Checkpoint Inhibitors therapeutic use, Lung pathology, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms pathology, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Male, Mice, Molecular Chaperones genetics, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Proto-Oncogene Proteins p21(ras) genetics, RNA, Guide, CRISPR-Cas Systems genetics, RNA, Small Interfering metabolism, RNA-Seq, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Tumor Suppressor Protein p53 genetics, Adenocarcinoma of Lung drug therapy, Cell Cycle Proteins metabolism, Drug Resistance, Neoplasm genetics, Immune Checkpoint Inhibitors pharmacology, Lung Neoplasms drug therapy, Molecular Chaperones metabolism
- Abstract
Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS -mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a Kras
G12D / Trp53-/- LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. Asf1a deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD. See related commentary by Menzel and Black, p. 179 . This article is highlighted in the In This Issue feature, p. 161 ., (©2019 American Association for Cancer Research.)- Published
- 2020
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23. Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.
- Author
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Xu-Monette ZY, Xiao M, Au Q, Padmanabhan R, Xu B, Hoe N, Rodríguez-Perales S, Torres-Ruiz R, Manyam GC, Visco C, Miao Y, Tan X, Zhang H, Tzankov A, Wang J, Dybkær K, Tam W, You H, Bhagat G, Hsi ED, Ponzoni M, Ferreri AJM, Møller MB, Piris MA, van Krieken JH, Winter JN, Westin JR, Pham LV, Medeiros LJ, Rassidakis GZ, Li Y, Freeman GJ, and Young KH
- Subjects
- Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Killer Cells, Natural immunology, Middle Aged, Phenotype, Prednisone therapeutic use, Prognosis, Rituximab therapeutic use, T-Lymphocytes immunology, Vincristine therapeutic use, B7-H1 Antigen immunology, CTLA-4 Antigen immunology, Lymphoma, Large B-Cell, Diffuse immunology, Programmed Cell Death 1 Receptor immunology, Tumor Microenvironment immunology
- Abstract
PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8
+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+ CD20+ cells proximal (indicates interaction) to PD-1+ CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+ /PD-L1+ patients with unfavorable prognosis and implication of LILRA / B, IDO1, CHI3L1 , and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab-CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies., (©2019 American Association for Cancer Research.)- Published
- 2019
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24. BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras -Mutant Non-Small Cell Lung Cancer.
- Author
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Adeegbe DO, Liu S, Hattersley MM, Bowden M, Zhou CW, Li S, Vlahos R, Grondine M, Dolgalev I, Ivanova EV, Quinn MM, Gao P, Hammerman PS, Bradner JE, Diehl JA, Rustgi AK, Bass AJ, Tsirigos A, Freeman GJ, Chen H, and Wong KK
- Subjects
- Adoptive Transfer, Animals, Carcinoma, Non-Small-Cell Lung immunology, Cytokines immunology, Lung Neoplasms immunology, Mice, Nude, Mice, Transgenic, Mutation, Proto-Oncogene Proteins p21(ras) genetics, T-Lymphocytes immunology, Tumor Suppressor Protein p53 deficiency, Azepines therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Nuclear Proteins antagonists & inhibitors, Programmed Cell Death 1 Receptor antagonists & inhibitors, Triazoles therapeutic use
- Abstract
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS- mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS -mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. Treatment with BET bromodomain inhibitors is beneficial for hematologic malignancies, and they have Treg-disruptive effects in a non-small cell lung cancer (NSCLC) model. Targeting PD-1-inhibitory signals through PD-1 antibody blockade also has substantial therapeutic impact in lung cancer, although these outcomes are limited to a minority of patients. We hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote a robust antitumor response in lung cancer. In the present study, using Kras
+/LSL-G12D ; Trp53L/L (KP) mouse models of NSCLC, we identified cooperative effects between JQ1 and PD-1 antibody. The numbers of tumor-infiltrating Tregs were reduced and activation of tumor-infiltrating T cells, which had a T-helper type 1 (Th1) cytokine profile, was enhanced, underlying their improved effector function. Furthermore, lung tumor-bearing mice treated with this combination showed robust and long-lasting antitumor responses compared with either agent alone, culminating in substantial improvement in the overall survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Cancer Immunol Res; 6(10); 1234-45. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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25. PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface.
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Chaudhri A, Xiao Y, Klee AN, Wang X, Zhu B, and Freeman GJ
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- Animals, Binding Sites, Binding, Competitive immunology, CD28 Antigens metabolism, CTLA-4 Antigen metabolism, Colonic Neoplasms immunology, Mice, Models, Immunological, Myeloid Cells immunology, Programmed Cell Death 1 Receptor metabolism, B7-1 Antigen metabolism, B7-H1 Antigen metabolism
- Abstract
Programmed death ligand 1 (PD-L1)-mediated immunosuppression regulates peripheral tolerance and is often co-opted by tumors to evade immune attack. PD-L1 binds to PD-1 but also binds to B7-1 (CD80) to regulate T-cell function. The binding interaction of PD-L1 with B7-1 and its functional role need further investigation to understand differences between PD-1 and PD-L1 tumor immunotherapy. We examined the molecular orientation of PD-L1 binding to B7-1 using cell-to-cell binding assays, ELISA, and flow cytometry. As expected, PD-L1-transfected cells bound to PD-1-transfected cells, and B7-1 cells bound to CD28 or CTLA-4-transfected cells; however, PD-L1 cells did not bind to B7-1 cells. By ELISA and flow cytometry with purified proteins, we found PD-L1 and B7-1 had a strong binding interaction only when PD-L1 was flexible. Soluble PD-1 and B7-1 competed for binding to PD-L1. Binding of native PD-L1 and B7-1 in cis on the same cell surface was demonstrated with NanoBiT proximity assays. Thus, PD-L1-B7-1 interaction can occur in cis on the same cell but not in trans between two cells, which suggests a model in which PD-L1 can bend via its 11-amino acid, flexible stalk to bind to B7-1 in cis , in a manner that can competitively block the binding of PD-L1 to PD-1 or of B7-1 to CD28. This binding orientation emphasizes the functional importance of coexpression of PD-L1 and B7-1 on the same cell. We found such coexpression on tumor-infiltrating myeloid cells. Our findings may help better utilize these pathways in cancer immunotherapy. Cancer Immunol Res; 6(8); 921-9. ©2018 AACR ., (©2018 American Association for Cancer Research.)
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- 2018
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26. Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.
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Jenkins RW, Aref AR, Lizotte PH, Ivanova E, Stinson S, Zhou CW, Bowden M, Deng J, Liu H, Miao D, He MX, Walker W, Zhang G, Tian T, Cheng C, Wei Z, Palakurthi S, Bittinger M, Vitzthum H, Kim JW, Merlino A, Quinn M, Venkataramani C, Kaplan JA, Portell A, Gokhale PC, Phillips B, Smart A, Rotem A, Jones RE, Keogh L, Anguiano M, Stapleton L, Jia Z, Barzily-Rokni M, Cañadas I, Thai TC, Hammond MR, Vlahos R, Wang ES, Zhang H, Li S, Hanna GJ, Huang W, Hoang MP, Piris A, Eliane JP, Stemmer-Rachamimov AO, Cameron L, Su MJ, Shah P, Izar B, Thakuria M, LeBoeuf NR, Rabinowits G, Gunda V, Parangi S, Cleary JM, Miller BC, Kitajima S, Thummalapalli R, Miao B, Barbie TU, Sivathanu V, Wong J, Richards WG, Bueno R, Yoon CH, Miret J, Herlyn M, Garraway LA, Van Allen EM, Freeman GJ, Kirschmeier PT, Lorch JH, Ott PA, Hodi FS, Flaherty KT, Kamm RD, Boland GM, Wong KK, Dornan D, Paweletz CP, and Barbie DA
- Subjects
- Animals, Cell Culture Techniques, Cell Line, Tumor, Cytokines metabolism, Drug Resistance, Neoplasm, Flow Cytometry, Humans, Immunohistochemistry, Immunophenotyping, Mice, Microfluidic Analytical Techniques, Programmed Cell Death 1 Receptor metabolism, Spheroids, Cellular, Time-Lapse Imaging, Tumor Cells, Cultured, Antineoplastic Agents, Immunological pharmacology, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens. Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR. See related commentary by Balko and Sosman, p. 143 See related article by Deng et al., p. 216 This article is highlighted in the In This Issue feature, p. 127 ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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27. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.
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Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, Ivanova E, Paweletz CP, Bowden M, Zhou CW, Herter-Sprie GS, Sorrentino JA, Bisi JE, Lizotte PH, Merlino AA, Quinn MM, Bufe LE, Yang A, Zhang Y, Zhang H, Gao P, Chen T, Cavanaugh ME, Rode AJ, Haines E, Roberts PJ, Strum JC, Richards WG, Lorch JH, Parangi S, Gunda V, Boland GM, Bueno R, Palakurthi S, Freeman GJ, Ritz J, Haining WN, Sharpless NE, Arthanari H, Shapiro GI, Barbie DA, Gray NS, and Wong KK
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents, Immunological pharmacology, Cell Line, Tumor, Humans, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Neoplasms diagnosis, Neoplasms genetics, Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, T-Lymphocytes metabolism, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Neoplasms immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology
- Abstract
Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo , due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143 See related article by Jenkins et al., p. 196 This article is highlighted in the In This Issue feature, p. 127 ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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28. PD-1 Status in CD8 + T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer.
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Kansy BA, Concha-Benavente F, Srivastava RM, Jie HB, Shayan G, Lei Y, Moskovitz J, Moy J, Li J, Brandau S, Lang S, Schmitt NC, Freeman GJ, Gooding WE, Clump DA, and Ferris RL
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cells, Cultured, Disease Models, Animal, Disease-Free Survival, Gene Expression drug effects, Head and Neck Neoplasms complications, Head and Neck Neoplasms immunology, Humans, Interferon-gamma immunology, Interferon-gamma metabolism, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Inbred C57BL, Outcome Assessment, Health Care methods, Outcome Assessment, Health Care statistics & numerical data, Papillomavirus Infections complications, Papillomavirus Infections immunology, Prognosis, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Proportional Hazards Models, Antibodies, Monoclonal therapeutic use, CD8-Positive T-Lymphocytes drug effects, Head and Neck Neoplasms drug therapy, Papillomavirus Infections drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1
+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients ( P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TILs were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence ( P < 0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1-based immunotherapy. Cancer Res; 77(22); 6353-64. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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29. Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer.
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Masugi Y, Nishihara R, Hamada T, Song M, da Silva A, Kosumi K, Gu M, Shi Y, Li W, Liu L, Nevo D, Inamura K, Cao Y, Liao X, Nosho K, Chan AT, Giannakis M, Bass AJ, Hodi FS, Freeman GJ, Rodig SJ, Fuchs CS, Qian ZR, Nowak JA, and Ogino S
- Subjects
- Aged, Colorectal Neoplasms microbiology, DNA, Bacterial, Female, Fusobacterium nucleatum genetics, Humans, Male, Middle Aged, Colorectal Neoplasms immunology, Lymphocytes immunology, Programmed Cell Death 1 Ligand 2 Protein immunology
- Abstract
Expression of the immune checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274 ) contributes to suppression of antitumor T cell-mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2 ) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by IHC in 823 colon and rectal carcinoma cases within two U.S.-nationwide cohort studies and categorized tumors into quartiles according to the percentage of PDCD1LG2-expressing carcinoma cells. We conducted multivariable ordinal logistic regression analysis to assess the associations of tumor PDCD1LG2 expression with Crohn-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, or tumor-infiltrating lymphocytes, controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF , and PIK3CA mutations. Tumor PDCD1LG2 expression was inversely associated with Crohn-like lymphoid reaction ( P
trend = 0.0003). For a unit increase in the three-tiered ordinal categories of Crohn-like lymphoid reaction, a multivariable OR in the highest (vs. lowest) quartile of the percentage of PDCD1LG2-expressing tumor cells was 0.38 (95% confidence interval, 0.22-0.67). Tumor PDCD1LG2 expression was not associated with peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, or patient survival ( Ptrend > 0.13). Thus, tumor PDCD1LG2 expression is inversely associated with Crohn-like lymphoid reaction to colorectal cancer, suggesting a possible role of PDCD1LG2-expressing tumor cells in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis. Cancer Immunol Res; 5(11); 1046-55. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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30. Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition.
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Gil Del Alcazar CR, Huh SJ, Ekram MB, Trinh A, Liu LL, Beca F, Zi X, Kwak M, Bergholtz H, Su Y, Ding L, Russnes HG, Richardson AL, Babski K, Min Hui Kim E, McDonnell CH 3rd, Wagner J, Rowberry R, Freeman GJ, Dillon D, Sorlie T, Coussens LM, Garber JE, Fan R, Bobolis K, Allred DC, Jeong J, Park SY, Michor F, and Polyak K
- Subjects
- B7-H1 Antigen genetics, Biomarkers, Tumor genetics, Breast Neoplasms genetics, CD3 Complex genetics, Carcinoma, Ductal, Breast genetics, Carcinoma, Intraductal, Noninfiltrating genetics, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, Leukocyte Common Antigens genetics, Receptor, ErbB-2 genetics, Tumor Microenvironment, Breast Neoplasms immunology, Carcinoma, Ductal, Breast immunology, Carcinoma, Intraductal, Noninfiltrating immunology, Gene Expression Profiling methods, T-Lymphocytes immunology
- Abstract
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45
+ CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+ CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. ©2017 AACR. See related commentary by Speiser and Verdeil, p. 1062 This article is highlighted in the In This Issue feature, p. 1047 ., (©2017 American Association for Cancer Research.)- Published
- 2017
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31. Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.
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Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, Rodig S, Li J, Wu X, Butterfield LH, Piesche M, Manos MP, Eastman LM, Dranoff G, Freeman GJ, and Hodi FS
- Subjects
- Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Bevacizumab therapeutic use, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cytokines blood, Humans, Ipilimumab therapeutic use, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Protein Isoforms, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen blood, Biomarkers, Tumor blood, CTLA-4 Antigen antagonists & inhibitors, Melanoma blood
- Abstract
Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480-92. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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32. Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes.
- Author
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Sridharan V, Gjini E, Liao X, Chau NG, Haddad RI, Severgnini M, Hammerman P, El-Naggar A, Freeman GJ, Hodi FS, Rodig SJ, Dranoff G, and Schoenfeld JD
- Subjects
- B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Carcinoma, Adenoid Cystic pathology, Carcinoma, Adenoid Cystic therapy, Chemoradiotherapy, Female, Gene Expression Profiling, Humans, Immunohistochemistry, Immunophenotyping, Male, Neoplasm Metastasis, Programmed Cell Death 1 Ligand 2 Protein genetics, Programmed Cell Death 1 Ligand 2 Protein metabolism, Salivary Gland Neoplasms genetics, Salivary Gland Neoplasms immunology, Transcriptome, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Carcinoma, Adenoid Cystic genetics, Carcinoma, Adenoid Cystic immunology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism
- Abstract
Adenoid cystic carcinoma (ACC) is among the most lethal salivary gland tumors, with no treatments for metastatic disease that prolong survival. We examined tissue from 28 primary and metastatic ACC deposits obtained from 21 patients for infiltrating immune cells and PD-L1/PD-L2 expression and determined mRNA profiles of over 1,400 oncogenic and immune-related genes. We also assessed the effect of chemoradiation on immune mediators in a patient who had serial biopsies available. Most tumors expressed PD-L2 but had few infiltrating immune cells. Lack of immune-cell infiltrate was associated with expression of genes in the β-catenin/Wnt and PI3K pathways. Additionally, certain transcripts linked to growth and invasion were differentially expressed among primary and metastatic deposits. Chemoradiation appeared to increase CD8(+) effector T cells, decrease regulatory T cells, and promote a systemic humoral response. These data suggest a potential role for PD-L2 inhibition and immune modulation as treatment for patients with ACC. Cancer Immunol Res; 4(8); 679-87. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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33. Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer.
- Author
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Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, and Ferris RL
- Subjects
- B7-H1 Antigen analysis, Cell Line, Tumor, Epidermal Growth Factor pharmacology, Head and Neck Neoplasms virology, Humans, Killer Cells, Natural immunology, Papillomaviridae isolation & purification, B7-H1 Antigen physiology, ErbB Receptors physiology, Head and Neck Neoplasms immunology, Interferon-gamma physiology, Janus Kinase 2 physiology, STAT1 Transcription Factor physiology
- Abstract
Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors., (©2015 American Association for Cancer Research.)
- Published
- 2016
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34. STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.
- Author
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Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS, Buczkowski KA, Liu Y, Awad MM, Denning WL, Diao L, Wang J, Parra-Cuentas ER, Wistuba II, Soucheray M, Thai T, Asahina H, Kitajima S, Altabef A, Cavanaugh JD, Rhee K, Gao P, Zhang H, Fecci PE, Shimamura T, Hellmann MD, Heymach JV, Hodi FS, Freeman GJ, Barbie DA, Dranoff G, Hammerman PS, and Wong KK
- Subjects
- AMP-Activated Protein Kinase Kinases, AMP-Activated Protein Kinases, Animals, B7-H1 Antigen analysis, Humans, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mutation, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Cytokines biosynthesis, Lung Neoplasms immunology, Neutrophil Infiltration, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases physiology, T-Lymphocytes immunology, Tumor Microenvironment
- Abstract
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies., (©2016 American Association for Cancer Research.)
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- 2016
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35. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.
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Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, Wen PY, Van Den Abbeele AD, Hodi FS, Qin L, Kohl NE, Sharpe AH, Dranoff G, and Freeman GJ
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Female, Glioblastoma drug therapy, Glioblastoma mortality, Glioblastoma pathology, Immunity drug effects, Immunologic Memory drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Neoplasm Recurrence, Local, Neoplasm Staging, Tumor Burden drug effects, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, CTLA-4 Antigen antagonists & inhibitors, Glioblastoma immunology, Glioblastoma metabolism, Immunomodulation drug effects, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma., (©2015 American Association for Cancer Research.)
- Published
- 2016
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36. MicroRNA MIR21 and T Cells in Colorectal Cancer.
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Mima K, Nishihara R, Nowak JA, Kim SA, Song M, Inamura K, Sukawa Y, Masuda A, Yang J, Dou R, Nosho K, Baba H, Giovannucci EL, Bowden M, Loda M, Giannakis M, Bass AJ, Dranoff G, Freeman GJ, Chan AT, Fuchs CS, Qian ZR, and Ogino S
- Subjects
- Aged, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology, Female, Humans, Male, Middle Aged, Prospective Studies, Colorectal Neoplasms metabolism, MicroRNAs physiology, T-Lymphocytes immunology
- Abstract
The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated. Experimental evidence suggests that microRNA MIR21 (miR-21) suppresses antitumor T-cell-mediated immunity. Thus, we hypothesized that tumor MIR21 expression might be inversely associated with T-cell density in colorectal carcinoma tissue. Using 538 rectal and colon cancer cases from the Nurses' Health Study and the Health Professionals Follow-up Study, we measured tumor MIR21 expression by a quantitative reverse-transcription PCR assay. Densities of CD3(+), CD8(+), CD45RO (PTPRC)(+), and FOXP3(+) cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression (ordinal quartiles as a predictor variable) with T-cell density (ordinal quartiles as an outcome variable), adjusting for tumor molecular features, including microsatellite instability; CpG island methylator phenotype; KRAS, BRAF, and PIK3CA mutations; and LINE-1 methylation. We adjusted the two-sided α level to 0.012 for multiple hypothesis testing. Tumor MIR21 expression was inversely associated with densities of CD3(+) and CD45RO(+) cells (Ptrend < 0.0005). The multivariate odds ratio of the highest versus lowest quartile of MIR21 for a unit increase in quartile categories of CD3(+) or CD45RO(+) cells was 0.44 [95% confidence interval (CI), 0.28 to 0.68] or 0.41 (95% CI, 0.26-0.64), respectively. Our data support a possible role of tumor epigenetic deregulation by noncoding RNA in suppressing the antitumor T-cell-mediated adaptive immune response and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer., (©2015 American Association for Cancer Research.)
- Published
- 2016
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37. PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells.
- Author
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Mahoney KM, Sun H, Liao X, Hua P, Callea M, Greenfield EA, Hodi FS, Sharpe AH, Signoretti S, Rodig SJ, and Freeman GJ
- Subjects
- Antibodies, Monoclonal, Humanized immunology, Antibodies, Monoclonal, Humanized pharmacology, Cell Line, Tumor, Humans, Neoplasms pathology, Nivolumab, Protein Structure, Tertiary, Staining and Labeling, Tissue Embedding, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, B7-H1 Antigen immunology, Cell Membrane immunology, Neoplasms immunology, Programmed Cell Death 1 Receptor immunology
- Abstract
Blocking the programmed death-1 (PD-1) pathway has clinical benefit in metastatic cancer and has led to the approval of the mAbs pembrolizumab and nivolumab to treat melanoma and nivolumab for non-small cell lung cancer. Expression of PD-L1 on the cell surface of either tumor cells or infiltrating immune cells is associated with a higher likelihood of response to PD-1 blockade in multiple studies. Most mAbs to PD-L1 in use are directed to its extracellular domain and immunohistochemically stain tumor tissue with a mixture of cytoplasmic and membrane staining. Cytoplasmic staining obscures the interpretation of a positive reaction on the tumor cell membrane, and thus affects the accuracy of PD-L1 scoring systems. We developed a mAb to the cytoplasmic domain of PD-L1, 405.9A11 (9A11), which is both more selective for membranous PD-L1 and more sensitive in IHC and Western blotting, compared with previous mAbs specific for the PD-L1 extracellular domain. Here, we compare immunohistochemical staining patterns of PD-L1 expression in five types of tumors, using five PD-L1 mAbs: 9A11, 7G11, and three commercially available mAbs. We demonstrate that 9A11, as well as two other cytoplasmic domain-specific mAbs, E1L3N and SP142, can clearly delineate the membrane of PD-L1-positive cells in formalin-fixed paraffin-embedded tissue and facilitate interpretation of staining results., (©2015 American Association for Cancer Research.)
- Published
- 2015
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38. Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma.
- Author
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Derks S, Nason KS, Liao X, Stachler MD, Liu KX, Liu JB, Sicinska E, Goldberg MS, Freeman GJ, Rodig SJ, Davison JM, and Bass AJ
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Aged, Animals, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Barrett Esophagus genetics, Barrett Esophagus pathology, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Female, Gene Expression, Heterografts, Humans, Immunohistochemistry, Interleukin-13 metabolism, Interleukin-4 metabolism, Male, Mice, Middle Aged, Mucous Membrane pathology, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Programmed Cell Death 1 Ligand 2 Protein genetics, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, Reproducibility of Results, Signal Transduction, Tumor Burden, Adenocarcinoma metabolism, Barrett Esophagus metabolism, Esophageal Neoplasms metabolism, Mucous Membrane metabolism, Programmed Cell Death 1 Ligand 2 Protein metabolism
- Abstract
Esophageal adenocarcinoma is an increasingly common disease with a dismal 5-year survival rate of 10% to 15%. In the first systematic evaluation of the PD-1 pathway in esophageal adenocarcinoma, we identify expression of PD-L2 in cancer cells in 51.7% of esophageal adenocarcinomas. Epithelial PD-L1 was expressed on only 2% of cases, although PD-L1(+) immune cells were observed in 18% of esophageal adenocarcinomas. We also evaluated expression in the precursor lesion of esophageal adenocarcinoma, Barrett's esophagus, which emerges following gastric reflux-induced esophageal inflammation, and found PD-L2 expression in Barrett's esophagus but not in non-Barrett's esophagus esophagitis. Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines. These results suggest that the inflammatory environment in Barrett's esophagus and esophageal adenocarcinoma may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in esophageal adenocarcinomas with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials., (©2015 American Association for Cancer Research.)
- Published
- 2015
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39. Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma.
- Author
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Callea M, Albiges L, Gupta M, Cheng SC, Genega EM, Fay AP, Song J, Carvo I, Bhatt RS, Atkins MB, Hodi FS, Choueiri TK, McDermott DF, Freeman GJ, and Signoretti S
- Subjects
- Adult, Aged, Aged, 80 and over, B7-H1 Antigen genetics, Carcinoma, Renal Cell diagnosis, Cell Membrane metabolism, Cohort Studies, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Male, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Prognosis, B7-H1 Antigen metabolism, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Kidney Neoplasms metabolism, Kidney Neoplasms pathology
- Abstract
PD-L1 expression in primary clear-cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11 of 53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (P = 0.51). Tumor cell PD-L1 positivity was associated with higher T stage (P = 0.03) and higher Fuhrman nuclear grade (P < 0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (P < 0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (P = 0.82). The heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as a predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, because PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false-negative results, these areas should be specifically selected for assessment., (©2015 American Association for Cancer Research.)
- Published
- 2015
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40. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy.
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Xiao Y and Freeman GJ
- Subjects
- Humans, Cell Cycle Checkpoints, Colonic Neoplasms genetics, Colonic Neoplasms immunology, Microsatellite Instability, Tumor Microenvironment genetics, Tumor Microenvironment immunology
- Abstract
The microsatellite instable (MSI) subset of colorectal cancer exhibits an active Th1/CTL immune microenvironment, probably due to recognition of a high number of tumor neoantigens. However, the high expression of checkpoint molecules PD-1, PD-L1, CTLA-4, LAG-3, and IDO in MSI colorectal cancer distinguishes MSI from microsatellite stable colorectal cancer and creates an immunosuppressive microenvironment that may help MSI tumors evade immune destruction by the infiltrating immune cells. Though colorectal cancer does not have a good response rate to PD-1 pathway immunotherapy, these results suggest that the MSI subset of colorectal cancer is a particularly good candidate for checkpoint immunotherapy., (©2015 American Association for Cancer Research.)
- Published
- 2015
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41. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.
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Cooper ZA, Juneja VR, Sage PT, Frederick DT, Piris A, Mitra D, Lo JA, Hodi FS, Freeman GJ, Bosenberg MW, McMahon M, Flaherty KT, Fisher DE, Sharpe AH, and Wargo JA
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antigens, Neoplasm metabolism, B7-H1 Antigen antagonists & inhibitors, CD8-Positive T-Lymphocytes immunology, CTLA-4 Antigen antagonists & inhibitors, Cell Line, Tumor, Cytokines biosynthesis, Dose-Response Relationship, Drug, Humans, Immunocompetence, Indoles administration & dosage, Ipilimumab, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Male, Melanoma pathology, Melanoma secondary, Mice, Inbred C57BL, Middle Aged, Sulfonamides administration & dosage, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Tumor Escape drug effects, Tumor Escape immunology, Vemurafenib, Xenograft Model Antitumor Assays methods, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Melanoma drug therapy, Melanoma immunology, Proto-Oncogene Proteins B-raf antagonists & inhibitors
- Abstract
BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy., (©2014 American Association for Cancer Research.)
- Published
- 2014
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42. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.
- Author
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Duraiswamy J, Freeman GJ, and Coukos G
- Subjects
- Animals, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen immunology, CD8-Positive T-Lymphocytes physiology, Carcinoma, Ovarian Epithelial, Cells, Cultured, Drug Evaluation, Preclinical, Drug Synergism, Female, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating pathology, Lymphocytes, Tumor-Infiltrating physiology, Mice, Mice, Inbred C57BL, Neoplasms, Glandular and Epithelial mortality, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Programmed Cell Death 1 Receptor immunology, Signal Transduction immunology, Antibodies administration & dosage, Antineoplastic Agents administration & dosage, CD8-Positive T-Lymphocytes drug effects, Immunotherapy methods, Neoplasms, Glandular and Epithelial immunology, Neoplasms, Glandular and Epithelial therapy, Ovarian Neoplasms immunology, Ovarian Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.
- Published
- 2013
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43. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
- Author
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Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, Wilkerson MD, Fecci PE, Butaney M, Reibel JB, Soucheray M, Cohoon TJ, Janne PA, Meyerson M, Hayes DN, Shapiro GI, Shimamura T, Sholl LM, Rodig SJ, Freeman GJ, Hammerman PS, Dranoff G, and Wong KK
- Subjects
- Animals, B7-H1 Antigen genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, ErbB Receptors genetics, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms metabolism, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oncogenes, Programmed Cell Death 1 Receptor genetics, Signal Transduction, Tumor Microenvironment, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung immunology, Cytokines metabolism, ErbB Receptors metabolism, Lung Neoplasms immunology, Programmed Cell Death 1 Receptor metabolism, T-Lymphocytes immunology, Tumor Escape
- Abstract
Unlabelled: The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition., Significance: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape., (©2013 AACR.)
- Published
- 2013
- Full Text
- View/download PDF
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