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2. FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer

Author

Yifan Tai, Angela Chow, Seoyoung Han, Courtney Coker, Wanchao Ma, Yifan Gu, Valeria Estrada Navarro, Manoj Kandpal, Hanina Hibshoosh, Kevin Kalinsky, Katia Manova-Todorova, Anton Safonov, Elaine M Walsh, Mark Robson, Larry Norton, Richard Baer, Taha Merghoub, Anup K Biswas, and Swarnali Acharyya

Subjects
FLT1, VEGFR1, Breast Cancer, PARP-Inhibitor-Resistance, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.

Published
2024
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3. Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models

Author

Verma, Svena, Budhu, Sadna, Serganova, Inna, Dong, Lauren, Mangarin, Levi M., Khan, Jonathan F., Bah, Mamadou A., Assouvie, Anais, Marouf, Yacine, Schulze, Isabell, Zappasodi, Roberta, Wolchok, Jedd D., and Merghoub, Taha

Subjects
Physiological aspects, Models, Research, Dosage and administration, Health aspects, Glucose -- Health aspects, Lactate dehydrogenase -- Health aspects, Tumors -- Models -- Physiological aspects, Medical research, Immune response -- Research, Enzyme inhibitors -- Dosage and administration -- Physiological aspects, Medicine, Experimental, Dextrose -- Health aspects
Abstract

Introduction The Warburg effect describes the propensity of cancer cells to favor the conversion of glucose to lactate for energy production, even in the presence of oxygen (1, 2). In [...], Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Published
2024
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4. TYRP1 directed CAR T cells control tumor progression in preclinical melanoma models

Author

Christopher S. Hackett, Daniel Hirschhorn, Meixian S. Tang, Terence J. Purdon, Yacine Marouf, Alessandra Piersigilli, Narasimhan P. Agaram, Cailian Liu, Sara E. Schad, Elisa de Stanchina, Sarwish Rafiq, Sebastien Monette, Jedd D. Wolchok, Taha Merghoub, and Renier J. Brentjens

Subjects
MT: Regular Issue, melanoma, acral, uveal, chimeric antigen receptor, adoptive cellular therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Despite therapeutic efficacy observed with immune checkpoint blockade in advanced melanoma, many tumors do not respond to treatment, representing a need for new therapies. Here, we have generated chimeric antigen receptor (CAR) T cells targeting TYRP1, a melanoma differentiation antigen expressed on the surface of melanomas, including rare acral and uveal melanomas. TYRP1-targeted CAR T cells demonstrate antigen-specific activation and cytotoxic activity in vitro and in vivo against human melanomas independent of the MHC alleles and expression. In addition, the toxicity to pigmented normal tissues observed with T lymphocytes expressing TYRP1-targeted TCRs was not observed with TYRP1-targeted CAR T cells. Anti-TYRP1 CAR T cells provide a novel means to target advanced melanomas, serving as a platform for the development of similar novel therapeutic agents and as a tool to interrogate the immunobiology of melanomas.

Published
2024
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5. Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma

Author

Marasco, Michelangelo, Kumar, Dinesh, Seale, Tessa, Borrego, Santiago Garcia, Kaplun, Esther, Aricescu, Ilinca, Cole, Soren, Qeriqi, Besnik, Qiu, Juan, Chen, Xiaoping, Bahr, Amber, Fidele, Deborah, Hofmann, Marco H., Gerlach, Daniel, Savarese, Fabio, Merghoub, Taha, Wolchok, Jedd D., Yao, Zhan, de Stanchina, Elisa, Solit, David, Misale, Sandra, and Rosen, Neal

Published
2024
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7. Comparative study of immune response to local tumor destruction modalities in a murine breast cancer model

Author

Sadna Budhu, Kwanghee Kim, Wesley Yip, Stephen La Rosa, Sylvia Jebiwott, Liqun Cai, Aliya Holland, Jasmine Thomas, Dina Preise, Alex Somma, Benjamin Gordon, Avigdor Scherz, Jedd D. Wolchok, Joseph Erinjeri, Taha Merghoub, and Jonathan A. Coleman

Subjects
radiation therapy, vascular photodynamic therapy, cryoablation, immune checkpoint blockade, breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IntroductionImmunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade.MethodsHere, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed.ResultsWe observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery.ConclusionThese data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT.

Published
2024
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9. Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Author

Memon, Danish, Schoenfeld, Adam J., Ye, Darwin, Fromm, George, Rizvi, Hira, Zhang, Xiang, Keddar, Mohamed Reda, Mathew, Divij, Yoo, Kyung Jin, Qiu, Jingya, Lihm, Jayon, Miriyala, Jayalaksmi, Sauter, Jennifer L., Luo, Jia, Chow, Andrew, Bhanot, Umesh K., McCarthy, Caroline, Vanderbilt, Chad M., Liu, Cailian, Abu-Akeel, Mohsen, Plodkowski, Andrew J., McGranahan, Nicholas, Łuksza, Marta, Greenbaum, Benjamin D., Merghoub, Taha, Achour, Ikbel, Barrett, J. Carl, Stewart, Ross, Beltrao, Pedro, Schreiber, Taylor H., Minn, Andy J., Miller, Martin L., and Hellmann, Matthew D.

Published
2024
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10. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Author

Rojas, Luis A., Sethna, Zachary, Soares, Kevin C., Olcese, Cristina, Pang, Nan, Patterson, Erin, Lihm, Jayon, Ceglia, Nicholas, Guasp, Pablo, Chu, Alexander, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Ruan, Jennifer, Amisaki, Masataka, Zebboudj, Abderezak, Odgerel, Zagaa, Payne, George, Derhovanessian, Evelyna, Müller, Felicitas, Rhee, Ina, Yadav, Mahesh, Dobrin, Anton, Sadelain, Michel, Łuksza, Marta, Cohen, Noah, Tang, Laura, Basturk, Olca, Gönen, Mithat, Katz, Seth, Do, Richard Kinh, Epstein, Andrew S., Momtaz, Parisa, Park, Wungki, Sugarman, Ryan, Varghese, Anna M., Won, Elizabeth, Desai, Avni, Wei, Alice C., D’Angelica, Michael I., Kingham, T. Peter, Mellman, Ira, Merghoub, Taha, Wolchok, Jedd D., Sahin, Ugur, Türeci, Özlem, Greenbaum, Benjamin D., Jarnagin, William R., Drebin, Jeffrey, O’Reilly, Eileen M., and Balachandran, Vinod P.

Published
2023
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11. Preoperative immune checkpoint inhibition and cryoablation in early-stage breast cancer

Author

Elizabeth Comen, Sadna Budhu, Yuval Elhanati, David Page, Teresa Rasalan-Ho, Erika Ritter, Phillip Wong, George Plitas, Sujata Patil, Edi Brogi, Maxine Jochelson, Yolanda Bryce, Stephen B. Solomon, Larry Norton, Taha Merghoub, and Heather L. McArthur

Subjects
Health sciences, Oncology, Immunology, Science
Abstract

Summary: Local cryoablation can engender systemic immune activation/anticancer responses in tumors otherwise resistant to immune checkpoint blockade (ICB). We evaluated the safety/tolerability of preoperative cryoablation plus ipilimumab and nivolumab in 5 early-stage/resectable breast cancers. The primary endpoint was met when all 5 patients underwent standard-of-care primary breast surgery undelayedly. Three patients developed transient hyperthyroidism; one developed grade 4 liver toxicity (resolved with supportive management). We compared this strategy with cryoablation and/or ipilimumab. Dual ICB plus cryoablation induced higher expression of T cell activation markers and serum Th1 cytokines and reduced immunosuppressive serum CD4+PD-1hi T cells, improving effector-to-suppressor T cell ratio. After dual ICB and before cryoablation, T cell receptor sequencing of 4 patients showed increased T cell clonality. In this small subset of patients, we provide preliminary evidence that preoperative cryoablation plus ipilimumab and nivolumab is feasible, inducing systemic adaptive immune activation potentially more robust than cryoablation with/without ipilimumab.

Published
2024
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12. Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non–Small Cell Lung Cancer

Author

Luo, Jia, Martucci, Victoria L, Quandt, Zoe, Groha, Stefan, Murray, Megan H, Lovly, Christine M, Rizvi, Hira, Egger, Jacklynn V, Plodkowski, Andrew J, Abu-Akeel, Mohsen, Schulze, Isabell, Merghoub, Taha, Cardenas, Eduardo, Huntsman, Scott, Li, Min, Hu, Donglei, Gubens, Matthew A, Gusev, Alexander, Aldrich, Melinda C, Hellmann, Matthew D, and Ziv, Elad

Subjects
Prevention, Cancer, Genetics, Clinical Research, Lung, Human Genome, Good Health and Well Being, Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Lung Neoplasms, Male, Middle Aged, Retrospective Studies, Risk Assessment, Thyroid Diseases, Treatment Outcome, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeGenetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE).Experimental designIn patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI.ResultsAmong 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit.ConclusionsThyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.

Published
2021

14. 878 T cell immunotherapies recruit and activate neutrophils to eliminate tumor antigen escape variants

Author

David Ng, Katherine S Panageas, Jedd D Wolchok, Taha Merghoub, Sadna Budhu, Olivier De Henau, Yanyun Li, Billel Gasmi, Cailian Liu, Sara Schad, Rebekka Duhen, Andrew D Weinberg, Mathieu Gigoux, David Redmond, David Schroder, Andrew Chow, Daniel Hirschhorn, Lukas kraehenbuehl, Isabell Schulze, Aliya Holland, Jean Albrengues, Mikala Egeblad, Arshi Arora, Xue-Yan He, Linda Hamadene, Travis Hollmann, Jacob M Ricca, Levi Mark B Mangarin, Anne-Laure Flamar, Heyjin Choi, Czrina A Cortez, Allison Betof Warner, Gabrielle A Rizzuto, and Christine N Spencer

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2023
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18. MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Author

Qian, Yu, Galan-Cobo, Ana, Guijarro, Irene, Dang, Minghao, Molkentine, David, Poteete, Alissa, Zhang, Fahao, Wang, Qi, Wang, Jing, Parra, Edwin, Panda, Apekshya, Fang, Jacy, Skoulidis, Ferdinandos, Wistuba, Ignacio I., Verma, Svena, Merghoub, Taha, Wolchok, Jedd D., Wong, Kwok-Kin, DeBerardinis, Ralph J., Minna, John D., Vokes, Natalie I., Meador, Catherine B., Gainor, Justin F., Wang, Linghua, Reuben, Alexandre, and Heymach, John V.

Published
2023
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19. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

Author

Galluzzi, Lorenzo, Vitale, Ilio, Warren, Sarah, Adjemian, Sandy, Agostinis, Patrizia, Martinez, Aitziber Buqué, Chan, Timothy A, Coukos, George, Demaria, Sandra, Deutsch, Eric, Draganov, Dobrin, Edelson, Richard L, Formenti, Silvia C, Fucikova, Jitka, Gabriele, Lucia, Gaipl, Udo S, Gameiro, Sofia R, Garg, Abhishek D, Golden, Encouse, Han, Jian, Harrington, Kevin J, Hemminki, Akseli, Hodge, James W, Hossain, Dewan Md Sakib, Illidge, Tim, Karin, Michael, Kaufman, Howard L, Kepp, Oliver, Kroemer, Guido, Lasarte, Juan Jose, Loi, Sherene, Lotze, Michael T, Manic, Gwenola, Merghoub, Taha, Melcher, Alan A, Mossman, Karen L, Prosper, Felipe, Rekdal, Øystein, Rescigno, Maria, Riganti, Chiara, Sistigu, Antonella, Smyth, Mark J, Spisek, Radek, Stagg, John, Strauss, Bryan E, Tang, Daolin, Tatsuno, Kazuki, van Gool, Stefaan W, Vandenabeele, Peter, Yamazaki, Takahiro, Zamarin, Dmitriy, Zitvogel, Laurence, Cesano, Alessandra, and Marincola, Francesco M

Subjects
Inflammatory and immune system, Consensus, Guidelines as Topic, Humans, Immunogenic Cell Death, Molecular Biology, oncology, immunology, molecular biology
Abstract

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

Published
2020

20. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

Author

Pai, Joy A., Hellmann, Matthew D., Sauter, Jennifer L., Mattar, Marissa, Rizvi, Hira, Woo, Hyung Jun, Shah, Nisargbhai, Nguyen, Evelyn M., Uddin, Fathema Z., Quintanal-Villalonga, Alvaro, Chan, Joseph M., Manoj, Parvathy, Allaj, Viola, Baine, Marina K., Bhanot, Umesh K., Jain, Mala, Linkov, Irina, Meng, Fanli, Brown, David, Chaft, Jamie E., Plodkowski, Andrew J., Gigoux, Mathieu, Won, Helen H., Sen, Triparna, Wells, Daniel K., Donoghue, Mark T.A., de Stanchina, Elisa, Wolchok, Jedd D., Loomis, Brian, Merghoub, Taha, Rudin, Charles M., Chow, Andrew, and Satpathy, Ansuman T.

Published
2023
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21. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants

Author

Hirschhorn, Daniel, Budhu, Sadna, Kraehenbuehl, Lukas, Gigoux, Mathieu, Schröder, David, Chow, Andrew, Ricca, Jacob M., Gasmi, Billel, De Henau, Olivier, Mangarin, Levi Mark B., Li, Yanyun, Hamadene, Linda, Flamar, Anne-Laure, Choi, Hyejin, Cortez, Czrina A., Liu, Cailian, Holland, Aliya, Schad, Sara, Schulze, Isabell, Betof Warner, Allison, Hollmann, Travis J., Arora, Arshi, Panageas, Katherine S., Rizzuto, Gabrielle A., Duhen, Rebekka, Weinberg, Andrew D., Spencer, Christine N., Ng, David, He, Xue-Yan, Albrengues, Jean, Redmond, David, Egeblad, Mikala, Wolchok, Jedd D., and Merghoub, Taha

Published
2023
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22. The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

Author

Chow, Andrew, Uddin, Fathema Z., Liu, Michael, Dobrin, Anton, Nabet, Barzin Y., Mangarin, Levi, Lavin, Yonit, Rizvi, Hira, Tischfield, Sam E., Quintanal-Villalonga, Alvaro, Chan, Joseph M., Shah, Nisargbhai, Allaj, Viola, Manoj, Parvathy, Mattar, Marissa, Meneses, Maximiliano, Landau, Rebecca, Ward, Mariana, Kulick, Amanda, Kwong, Charlene, Wierzbicki, Matthew, Yavner, Jessica, Egger, Jacklynn, Chavan, Shweta S., Farillas, Abigail, Holland, Aliya, Sridhar, Harsha, Ciampricotti, Metamia, Hirschhorn, Daniel, Guan, Xiangnan, Richards, Allison L., Heller, Glenn, Mansilla-Soto, Jorge, Sadelain, Michel, Klebanoff, Christopher A., Hellmann, Matthew D., Sen, Triparna, de Stanchina, Elisa, Wolchok, Jedd D., Merghoub, Taha, and Rudin, Charles M.

Published
2023
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23. Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant

Author

Ning Yang, Aitor Garcia, Cindy Meyer, Thomas Tuschl, Taha Merghoub, Jedd D. Wolchok, and Liang Deng

Subjects
Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2.

Published
2022
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24. In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response

Author

Aditi Sahu, Kivanc Kose, Lukas Kraehenbuehl, Candice Byers, Aliya Holland, Teguru Tembo, Anthony Santella, Anabel Alfonso, Madison Li, Miguel Cordova, Melissa Gill, Christi Fox, Salvador Gonzalez, Piyush Kumar, Amber Weiching Wang, Nicholas Kurtansky, Pratik Chandrani, Shen Yin, Paras Mehta, Cristian Navarrete-Dechent, Gary Peterson, Kimeil King, Stephen Dusza, Ning Yang, Shuaitong Liu, William Phillips, Pascale Guitera, Anthony Rossi, Allan Halpern, Liang Deng, Melissa Pulitzer, Ashfaq Marghoob, Chih-Shan Jason Chen, Taha Merghoub, and Milind Rajadhyaksha

Subjects
Science
Abstract

Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.

Published
2022
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26. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Author

Łuksza, Marta, Sethna, Zachary M., Rojas, Luis A., Lihm, Jayon, Bravi, Barbara, Elhanati, Yuval, Soares, Kevin, Amisaki, Masataka, Dobrin, Anton, Hoyos, David, Guasp, Pablo, Zebboudj, Abderezak, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Odgerel, Zagaa, Leung, Joanne, Kappagantula, Rajya, Makohon-Moore, Alvin, Johns, Amber, Gill, Anthony, Gigoux, Mathieu, Wolchok, Jedd, Merghoub, Taha, Sadelain, Michel, Patterson, Erin, Monasson, Remi, Mora, Thierry, Walczak, Aleksandra M., Cocco, Simona, Iacobuzio-Donahue, Christine, Greenbaum, Benjamin D., and Balachandran, Vinod P.

Published
2022
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27. Fundamental immune–oncogenicity trade-offs define driver mutation fitness

Author

Hoyos, David, Zappasodi, Roberta, Schulze, Isabell, Sethna, Zachary, de Andrade, Kelvin César, Bajorin, Dean F., Bandlamudi, Chaitanya, Callahan, Margaret K., Funt, Samuel A., Hadrup, Sine R., Holm, Jeppe S., Rosenberg, Jonathan E., Shah, Sohrab P., Vázquez-García, Ignacio, Weigelt, Britta, Wu, Michelle, Zamarin, Dmitriy, Campitelli, Laura F., Osborne, Edward J., Klinger, Mark, Robins, Harlan S., Khincha, Payal P., Savage, Sharon A., Balachandran, Vinod P., Wolchok, Jedd D., Hellmann, Matthew D., Merghoub, Taha, Levine, Arnold J., Łuksza, Marta, and Greenbaum, Benjamin D.

Published
2022
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28. Anatomic position determines oncogenic specificity in melanoma

Author

Weiss, Joshua M., Hunter, Miranda V., Cruz, Nelly M., Baggiolini, Arianna, Tagore, Mohita, Ma, Yilun, Misale, Sandra, Marasco, Michelangelo, Simon-Vermot, Theresa, Campbell, Nathaniel R., Newell, Felicity, Wilmott, James S., Johansson, Peter A., Thompson, John F., Long, Georgina V., Pearson, John V., Mann, Graham J., Scolyer, Richard A., Waddell, Nicola, Montal, Emily D., Huang, Ting-Hsiang, Jonsson, Philip, Donoghue, Mark T. A., Harris, Christopher C., Taylor, Barry S., Xu, Tianhao, Chaligné, Ronan, Shliaha, Pavel V., Hendrickson, Ronald, Jungbluth, Achim A., Lezcano, Cecilia, Koche, Richard, Studer, Lorenz, Ariyan, Charlotte E., Solit, David B., Wolchok, Jedd D., Merghoub, Taha, Rosen, Neal, Hayward, Nicholas K., and White, Richard M.

Published
2022
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29. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

Author

Jeppe Sejerø Holm, Samuel A. Funt, Annie Borch, Kamilla Kjærgaard Munk, Anne-Mette Bjerregaard, James L. Reading, Colleen Maher, Ashley Regazzi, Phillip Wong, Hikmat Al-Ahmadie, Gopa Iyer, Tripti Tamhane, Amalie Kai Bentzen, Nana Overgaard Herschend, Susan De Wolf, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Morten Nielsen, Jonathan E. Rosenberg, Dean F. Bajorin, and Sine Reker Hadrup

Subjects
Science
Abstract

Immune checkpoint blockade therapy is successful in a high proportion of cancer patients, but others remain unresponsive. Authors here show that therapeutic success might be predictable in metastatic bladder cancer by longitudinal analysis of the early neoantigen-specific CD8 T cell response in peripheral blood.

Published
2022
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30. Brain radiotherapy, tremelimumab-mediated CTLA-4-directed blockade +/− trastuzumab in patients with breast cancer brain metastases

Author

David B. Page, Kathryn Beal, Stefanie N. Linch, Kateri J. Spinelli, Micaela Rodine, Darragh Halpenny, Shanu Modi, Sujata Patil, Robert J. Young, Thomas Kaley, Taha Merghoub, David Redmond, Phillip Wong, Christopher A. Barker, Adi Diab, Larry Norton, and Heather L. McArthur

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Breast cancer brain metastases (BCBM) are a common and devastating complication of metastatic breast cancer with conventional systemic therapies demonstrating limited effectiveness. Consequently, radiotherapy (RT) ± surgery remains the cornerstone of BCBM management. Because preclinical and clinical evidence indicate that immune checkpoint blockade (ICB) may synergize with RT to promote systemic tumor regression, we explored the safety and efficacy of RT and concurrent tremelimumab-mediated cytotoxic T-lymphocyte associated protein 4 (CTLA-4) ICB with tremelimumab ± HER2-directed therapy with trastuzumab for BCBM. Eligible patients had BCBM indicated for brain RT. A Simon two-stage design was adopted to evaluate the efficacy of tremelimumab and RT in 20 patients with human epidermal growth factor receptor normal (HER2−) BCBM. The safety of concurrent RT, tremelimumab, and trastuzumab was evaluated in a cohort of 6 HER2+ patients. The primary endpoint was 12-week non-central nervous system (CNS) disease control rate (DCR). Secondary endpoints included safety, survival, and CNS response. Exploratory correlatives included characterization of peripheral blood immune responses among exceptional responders. Tremelimumab plus RT ± trastuzumab was tolerated with no treatment-related grade 4 adverse events reported. The 12-week non-CNS DCR was 10% (2/20) in the HER2− cohort and 33% (2/6) in the HER2+ cohort. One patient with HER2+ disease experienced a durable partial response with evidence of peripheral T-cell activation. Thus, tremelimumab and RT ± trastuzumab was tolerated. Although modest clinical activity was observed in the HER2- efficacy cohort, encouraging responses were observed in the HER2+ safety cohort. Consequently, a trial to determine efficacy in HER2+ BCBM is planned. Clinical Trial Registration Number: NCT02563925.

Published
2022
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32. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

Author

Holm, Jeppe Sejerø, Funt, Samuel A., Borch, Annie, Munk, Kamilla Kjærgaard, Bjerregaard, Anne-Mette, Reading, James L., Maher, Colleen, Regazzi, Ashley, Wong, Phillip, Al-Ahmadie, Hikmat, Iyer, Gopa, Tamhane, Tripti, Bentzen, Amalie Kai, Herschend, Nana Overgaard, De Wolf, Susan, Snyder, Alexandra, Merghoub, Taha, Wolchok, Jedd D., Nielsen, Morten, Rosenberg, Jonathan E., Bajorin, Dean F., and Hadrup, Sine Reker

Published
2022
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34. In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response

Author

Sahu, Aditi, Kose, Kivanc, Kraehenbuehl, Lukas, Byers, Candice, Holland, Aliya, Tembo, Teguru, Santella, Anthony, Alfonso, Anabel, Li, Madison, Cordova, Miguel, Gill, Melissa, Fox, Christi, Gonzalez, Salvador, Kumar, Piyush, Wang, Amber Weiching, Kurtansky, Nicholas, Chandrani, Pratik, Yin, Shen, Mehta, Paras, Navarrete-Dechent, Cristian, Peterson, Gary, King, Kimeil, Dusza, Stephen, Yang, Ning, Liu, Shuaitong, Phillips, William, Guitera, Pascale, Rossi, Anthony, Halpern, Allan, Deng, Liang, Pulitzer, Melissa, Marghoob, Ashfaq, Chen, Chih-Shan Jason, Merghoub, Taha, and Rajadhyaksha, Milind

Published
2022
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36. Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer

Author

Aditi Gupta, Sadna Budhu, Kelly Fitzgerald, Rachel Giese, Adam O. Michel, Aliya Holland, Luis Felipe Campesato, Jacques van Snick, Catherine Uyttenhove, Gerd Ritter, Jedd D. Wolchok, and Taha Merghoub

Subjects
Biology (General), QH301-705.5
Abstract

Gupta et al. demonstrate that targeting isoform-specific TGFβ leads to an increase in the anti-tumor response when compared to pan-TGFβ inhibition, due to enhanced CD8 T cell function. The authors also report that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control.

Published
2021
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37. In vivo optical imaging-guided targeted sampling for precise diagnosis and molecular pathology

Author

Aditi Sahu, Yuna Oh, Gary Peterson, Miguel Cordova, Cristian Navarrete-Dechent, Melissa Gill, Christi Alessi-Fox, Salvador Gonzalez, William Phillips, Steven Wilson, Reza Afzalneia, Raven Rose, Abu-Akeel Mohsen, Danielle Bello, Ashfaq Marghoob, Anthony Rossi, Jedd D. Wolchok, Taha Merghoub, Veronica Rotemberg, Chih-Shan Jason Chen, and Milind Rajadhyaksha

Subjects
Medicine, Science
Abstract

Abstract Conventional tissue sampling can lead to misdiagnoses and repeated biopsies. Additionally, tissue processed for histopathology suffers from poor nucleic acid quality and/or quantity for downstream molecular profiling. Targeted micro-sampling of tissue can ensure accurate diagnosis and molecular profiling in the presence of spatial heterogeneity, especially in tumors, and facilitate acquisition of fresh tissue for molecular analysis. In this study, we explored the feasibility of performing 1–2 mm precision biopsies guided by high-resolution reflectance confocal microscopy (RCM) and optical coherence tomography (OCT), and reflective metallic grids for accurate spatial targeting. Accurate sampling was confirmed with either histopathology or molecular profiling through next generation sequencing (NGS) in 9 skin cancers in 7 patients. Imaging-guided 1–2 mm biopsies enabled spatial targeting for in vivo diagnosis, feature correlation and depth assessment, which were confirmed with histopathology. In vivo 1-mm targeted biopsies achieved adequate quantity and high quality of DNA for next-generation sequencing. Subsequent mutational profiling was confirmed on 1 melanoma in situ and 2 invasive melanomas, using a 505-gene mutational panel called Memorial Sloan Kettering-Integrated mutational profiling of actionable cancer targets (MSK-IMPACT). Differential mutational landscapes, in terms of number and types of mutations, were found between invasive and in situ melanomas in a single patient. Our findings demonstrate feasibility of accurate sampling of regions of interest for downstream histopathological diagnoses and molecular pathology in both in vivo and ex vivo settings with broad diagnostic, therapeutic and research potential in cutaneous diseases accessible by RCM-OCT imaging.

Published
2021
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38. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Author

Lu, Sydney X., De Neef, Emma, Thomas, James D., Sabio, Erich, Rousseau, Benoit, Gigoux, Mathieu, Knorr, David A., Greenbaum, Benjamin, Elhanati, Yuval, Hogg, Simon J., Chow, Andrew, Ghosh, Arnab, Xie, Abigail, Zamarin, Dmitriy, Cui, Daniel, Erickson, Caroline, Singer, Michael, Cho, Hana, Wang, Eric, Lu, Bin, Durham, Benjamin H., Shah, Harshal, Chowell, Diego, Gabel, Austin M., Shen, Yudao, Liu, Jing, Jin, Jian, Rhodes, Matthew C., Taylor, Richard E., Molina, Henrik, Wolchok, Jedd D., Merghoub, Taha, Diaz, Luis A., Jr., Abdel-Wahab, Omar, and Bradley, Robert K.

Published
2021
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39. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors

Author

Xu, Shihao, Chaudhary, Omkar, Rodríguez-Morales, Patricia, Sun, Xiaoli, Chen, Dan, Zappasodi, Roberta, Xu, Ziyan, Pinto, Antonio F.M., Williams, April, Schulze, Isabell, Farsakoglu, Yagmur, Varanasi, Siva Karthik, Low, Jun Siong, Tang, Wenxi, Wang, Haiping, McDonald, Bryan, Tripple, Victoria, Downes, Michael, Evans, Ronald M., Abumrad, Nada A., Merghoub, Taha, Wolchok, Jedd D., Shokhirev, Maxim N., Ho, Ping-Chih, Witztum, Joseph L., Emu, Brinda, Cui, Guoliang, and Kaech, Susan M.

Published
2021
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40. Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity

Author

Chow, Andrew, Schad, Sara, Green, Michael D., Hellmann, Matthew D., Allaj, Viola, Ceglia, Nicholas, Zago, Giulia, Shah, Nisargbhai S., Sharma, Sai Kiran, Mattar, Marissa, Chan, Joseph, Rizvi, Hira, Zhong, Hong, Liu, Cailian, Bykov, Yonina, Zamarin, Dmitriy, Shi, Hongyu, Budhu, Sadna, Wohlhieter, Corrin, Uddin, Fathema, Gupta, Aditi, Khodos, Inna, Waninger, Jessica J., Qin, Angel, Markowitz, Geoffrey J., Mittal, Vivek, Balachandran, Vinod, Durham, Jennifer N., Le, Dung T., Zou, Weiping, Shah, Sohrab P., McPherson, Andrew, Panageas, Katherine, Lewis, Jason S., Perry, Justin S.A., de Stanchina, Elisa, Sen, Triparna, Poirier, John T., Wolchok, Jedd D., Rudin, Charles M., and Merghoub, Taha

Published
2021
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41. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Author

Caushi, Justina X., Zhang, Jiajia, Ji, Zhicheng, Vaghasia, Ajay, Zhang, Boyang, Hsiue, Emily Han-Chung, Mog, Brian J., Hou, Wenpin, Justesen, Sune, Blosser, Richard, Tam, Ada, Anagnostou, Valsamo, Cottrell, Tricia R., Guo, Haidan, Chan, Hok Yee, Singh, Dipika, Thapa, Sampriti, Dykema, Arbor G., Burman, Poromendro, Choudhury, Begum, Aparicio, Luis, Cheung, Laurene S., Lanis, Mara, Belcaid, Zineb, El Asmar, Margueritta, Illei, Peter B., Wang, Rulin, Meyers, Jennifer, Schuebel, Kornel, Gupta, Anuj, Skaist, Alyza, Wheelan, Sarah, Naidoo, Jarushka, Marrone, Kristen A., Brock, Malcolm, Ha, Jinny, Bush, Errol L., Park, Bernard J., Bott, Matthew, Jones, David R., Reuss, Joshua E., Velculescu, Victor E., Chaft, Jamie E., Kinzler, Kenneth W., Zhou, Shibin, Vogelstein, Bert, Taube, Janis M., Hellmann, Matthew D., Brahmer, Julie R., Merghoub, Taha, Forde, Patrick M., Yegnasubramanian, Srinivasan, Ji, Hongkai, Pardoll, Drew M., and Smith, Kellie N.

Published
2021
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43. Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized Actionable Pathways

Author

Lacouture, Mario E; https://orcid.org/0000-0002-4818-3710, Goleva, Elena; https://orcid.org/0000-0002-4685-9318, Shah, Neil; https://orcid.org/0000-0001-5752-6212, Rotemberg, Veronica; https://orcid.org/0000-0003-0639-2677, Kraehenbuehl, Lukas; https://orcid.org/0000-0001-5411-5661, Ketosugbo, Kwami F; https://orcid.org/0000-0003-1637-1941, Merghoub, Taha; https://orcid.org/0000-0002-1518-5111, Maier, Tara; https://orcid.org/0009-0001-7691-404X, Bang, Alexander; https://orcid.org/0000-0002-1700-2411, Gu, Stephanie; https://orcid.org/0000-0002-6416-785X, Salvador, Trina; https://orcid.org/0009-0009-2346-0660, Moy, Andrea P; https://orcid.org/0000-0001-5431-6682, Lyubchenko, Taras; https://orcid.org/0000-0001-9466-5916, Xiao, Olivia; https://orcid.org/0000-0002-3869-5894, Hall, Clifton F; https://orcid.org/0000-0002-5180-1014, Berdyshev, Evgeny; https://orcid.org/0000-0002-1376-0098, Crooks, James; https://orcid.org/0000-0002-0021-5701, Weight, Ryan; https://orcid.org/0009-0006-0982-2096, Kern, Jeffrey A; https://orcid.org/0000-0001-9709-9622, Leung, Donald Y M; https://orcid.org/0000-0002-0177-3844, Lacouture, Mario E; https://orcid.org/0000-0002-4818-3710, Goleva, Elena; https://orcid.org/0000-0002-4685-9318, Shah, Neil; https://orcid.org/0000-0001-5752-6212, Rotemberg, Veronica; https://orcid.org/0000-0003-0639-2677, Kraehenbuehl, Lukas; https://orcid.org/0000-0001-5411-5661, Ketosugbo, Kwami F; https://orcid.org/0000-0003-1637-1941, Merghoub, Taha; https://orcid.org/0000-0002-1518-5111, Maier, Tara; https://orcid.org/0009-0001-7691-404X, Bang, Alexander; https://orcid.org/0000-0002-1700-2411, Gu, Stephanie; https://orcid.org/0000-0002-6416-785X, Salvador, Trina; https://orcid.org/0009-0009-2346-0660, Moy, Andrea P; https://orcid.org/0000-0001-5431-6682, Lyubchenko, Taras; https://orcid.org/0000-0001-9466-5916, Xiao, Olivia; https://orcid.org/0000-0002-3869-5894, Hall, Clifton F; https://orcid.org/0000-0002-5180-1014, Berdyshev, Evgeny; https://orcid.org/0000-0002-1376-0098, Crooks, James; https://orcid.org/0000-0002-0021-5701, Weight, Ryan; https://orcid.org/0009-0006-0982-2096, Kern, Jeffrey A; https://orcid.org/0000-0001-9709-9622, and Leung, Donald Y M; https://orcid.org/0000-0002-0177-3844

Abstract

Purpose: Immune-related cutaneous adverse events (ircAEs) occur in ≥50% of patients treated with checkpoint inhibitors (CPI), but mechanisms are poorly understood. Experimental Design: Phenotyping/biomarker analyses were conducted in 200 patients on CPIs (139 with ircAEs, 61 without, control) to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip (STS) extracts and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. Results: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFN-gamma mRNA in patients with lichenoid (p<0.0001) and psoriasiform dermatitis (p<0.01) as compared to patients without ircAEs, while the highest IL-13 mRNA levels were detected in the eczema (p<0.0001, compared to control). IL-17A mRNA was selectively increased in psoriasiform (p<0.001), lichenoid (p<0.0001), bullous dermatitis (p<0.05) and MPR (p<0.001), compared to control. Distinct cytokine profiles were confirmed in STS and plasma. Analysis determined increased skin/plasma IL-4 cytokine in pruritus, skin IL-13 in eczema, plasma IL-5 and IL-31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2-cytokine targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. Conclusions: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.

Published
2024

44. Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade

Author

Arnab Ghosh, Judith Michels, Riccardo Mezzadra, Divya Venkatesh, Lauren Dong, Ricardo Gomez, Fadi Samaan, Yu-Jui Ho, Luis Felipe Campesato, Levi Mangarin, John Fak, Nathan Suek, Aliya Holland, Cailian Liu, Mohsen Abu-Akeel, Yonina Bykov, Hong Zhong, Kelly Fitzgerald, Sadna Budhu, Andrew Chow, Roberta Zappasodi, Katherine S. Panageas, Olivier de Henau, Marcus Ruscetti, Scott W. Lowe, Taha Merghoub, and Jedd D. Wolchok

Subjects
Oncology, Therapeutics, Medicine
Abstract

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule–based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

Published
2022
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45. Comparative study of immune response to local tumor destruction modalities in a murine breast cancer model.

Author

Budhu, Sadna, Kim, Kwanghee, Yip, Wesley, La Rosa, Stephen, Jebiwott, Sylvia, Cai, Liqun, Holland, Aliya, Thomas, Jasmine, Preise, Dina, Somma, Alex, Gordon, Benjamin, Scherz, Avigdor, Wolchok, Jedd D., Erinjeri, Joseph, Merghoub, Taha, and Coleman, Jonathan A.

Subjects
IMMUNE response, BREAST cancer, MYELOID cells, IMMUNE checkpoint proteins, CELL death
Abstract

Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade. Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed. Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of nontreated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery. Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction

Author

Khan, Aly A., Lugade, Amit, Lazic, Ana M. Mijalkovic, Frentzen, Angela A. Elizabeth, Tadmor, Arbel D., Sasson, Ariella S., Rao, Arjun A., Pei, Baikang, Schrörs, Barbara, Berent-Maoz, Beata, Carreno, Beatriz M., Song, Bin, Peters, Bjoern, Li, Bo, Higgs, Brandon W., Stevenson, Brian J., Iseli, Christian, Miller, Christopher A., Morehouse, Christopher A., Melief, Cornelis J.M., Puig-Saus, Cristina, van Beek, Daphne, Balli, David, Gfeller, David, Haussler, David, Jäger, Dirk, Cortes, Eduardo, Esaulova, Ekaterina, Sherafat, Elham, Arcila, Francisco, Bartha, Gabor, Liu, Geng, Coukos, George, Richard, Guilhem, Chang, Han, Si, Han, Zörnig, Inka, Xenarios, Ioannis, Mandoiu, Ion, Kooi, Irsan, Conway, James P., Kessler, Jan H., Greenbaum, Jason A., Perera, Jason F., Harris, Jason, Hundal, Jasreet, Shelton, Jennifer M., Wang, Jianmin, Wang, Jiaqian, Greshock, Joel, Blake, Jonathon, Szustakowski, Joseph, Kodysh, Julia, Forman, Juliet, Wei, Lei, Lee, Leo J., Fanchi, Lorenzo F., Slagter, Maarten, Lang, Maren, Mueller, Markus, Lower, Martin, Vormehr, Mathias, Artyomov, Maxim N., Kuziora, Michael, Princiotta, Michael, Bassani-Sternberg, Michal, Macabali, Mignonette, Kojicic, Milica R., Yang, Naibo, Raicevic, Nevena M. Ilic, Guex, Nicolas, Robine, Nicolas, Halama, Niels, Skundric, Nikola M., Milicevic, Ognjen S., Gellert, Pascal, Jongeneel, Patrick, Charoentong, Pornpimol, Srivastava, Pramod K., Tanden, Prateek, Shah, Priyanka, Hu, Qiang, Gupta, Ravi, Chen, Richard, Petit, Robert, Ziman, Robert, Hilker, Rolf, Shukla, Sachet A., Al Seesi, Sahar, Boyle, Sean M., Qiu, Si, Sarkizova, Siranush, Salama, Sofie, Liu, Song, Wu, Song, Sridhar, Sriram, Ketelaars, Steven L.C., Jhunjhunwala, Suchit, Shcheglova, Tatiana, Schuepbach, Thierry, Creasy, Todd H., Josipovic, Veliborka, Kovacevic, Vladimir B., Fu, Weixuan, Krebber, Willem-Jan, Hsu, Yi-Hsiang, Sebastian, Yinong, Yalcin, Zeynep Kosaloglu, Huang, Zhiqin, Wells, Daniel K., van Buuren, Marit M., Dang, Kristen K., Hubbard-Lucey, Vanessa M., Sheehan, Kathleen C.F., Campbell, Katie M., Lamb, Andrew, Ward, Jeffrey P., Sidney, John, Blazquez, Ana B., Rech, Andrew J., Zaretsky, Jesse M., Comin-Anduix, Begonya, Ng, Alphonsus H.C., Chour, William, Yu, Thomas V., Rizvi, Hira, Chen, Jia M., Manning, Patrice, Steiner, Gabriela M., Doan, Xengie C., Merghoub, Taha, Guinney, Justin, Kolom, Adam, Selinsky, Cheryl, Ribas, Antoni, Hellmann, Matthew D., Hacohen, Nir, Sette, Alessandro, Heath, James R., Bhardwaj, Nina, Ramsdell, Fred, Schreiber, Robert D., Schumacher, Ton N., Kvistborg, Pia, and Defranoux, Nadine A.

Published
2020
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47. Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition

Author

Nabet, Barzin Y., Esfahani, Mohammad S., Moding, Everett J., Hamilton, Emily G., Chabon, Jacob J., Rizvi, Hira, Steen, Chloe B., Chaudhuri, Aadel A., Liu, Chih Long, Hui, Angela B., Almanza, Diego, Stehr, Henning, Gojenola, Linda, Bonilla, Rene F., Jin, Michael C., Jeon, Young-Jun, Tseng, Diane, Liu, Cailian, Merghoub, Taha, Neal, Joel W., Wakelee, Heather A., Padda, Sukhmani K., Ramchandran, Kavitha J., Das, Millie, Plodkowski, Andrew J., Yoo, Christopher, Chen, Emily L., Ko, Ryan B., Newman, Aaron M., Hellmann, Matthew D., Alizadeh, Ash A., and Diehn, Maximilian

Published
2020
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48. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours

Author

Zappasodi, Roberta, Serganova, Inna, Cohen, Ivan J., Maeda, Masatomo, Shindo, Masahiro, Senbabaoglu, Yasin, Watson, McLane J., Leftin, Avigdor, Maniyar, Rachana, Verma, Svena, Lubin, Matthew, Ko, Myat, Mane, Mayuresh M., Zhong, Hong, Liu, Cailian, Ghosh, Arnab, Abu-Akeel, Mohsen, Ackerstaff, Ellen, Koutcher, Jason A., Ho, Ping-Chih, Delgoffe, Greg M., Blasberg, Ronald, Wolchok, Jedd D., and Merghoub, Taha

Published
2021
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49. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Lundqvist, Andreas, van Hoef, Vincent, Zhang, Xiaonan, Wennerberg, Erik, Lorent, Julie, Witt, Kristina, Sanz, Laia Masvidal, Liang, Shuo, Murray, Shannon, Larsson, Ola, Kiessling, Rolf, Mao, Yumeng, Sidhom, John-William, Bessell, Catherine A, Havel, Jonathan, Schneck, Jonathan, Chan, Timothy A, Sachsenmeier, Eliot, Woods, David, Berglund, Anders, Ramakrishnan, Rupal, Sodre, Andressa, Weber, Jeffrey, Zappasodi, Roberta, Li, Yanyun, Qi, Jingjing, Wong, Philip, Sirard, Cynthia, Postow, Michael, Newman, Walter, Koon, Henry, Velcheti, Vamsidhar, Callahan, Margaret K, Wolchok, Jedd D, Merghoub, Taha, Lum, Lawrence G, Choi, Minsig, Thakur, Archana, Deol, Abhinav, Dyson, Gregory, Shields, Anthony, Haymaker, Cara, Uemura, Marc, Murthy, Ravi, James, Marihella, Wang, Daqing, Brevard, Julie, Monaghan, Catherine, Swann, Suzanne, Geib, James, Cornfeld, Mark, Chunduru, Srinivas, Agrawal, Sudhir, Yee, Cassian, Wargo, Jennifer, Patel, Sapna P, Amaria, Rodabe, Tawbi, Hussein, Glitza, Isabella, Woodman, Scott, Hwu, Wen-Jen, Davies, Michael A, Hwu, Patrick, Overwijk, Willem W, Bernatchez, Chantale, Diab, Adi, Massarelli, Erminia, Segal, Neil H, Ribrag, Vincent, Melero, Ignacio, Gangadhar, Tara C, Urba, Walter, Schadendorf, Dirk, Ferris, Robert L, Houot, Roch, Morschhauser, Franck, Logan, Theodore, Luke, Jason J, Sharfman, William, Barlesi, Fabrice, Ott, Patrick A, Mansi, Laura, Kummar, Shivaani, Salles, Gilles, Carpio, Cecilia, Meier, Roland, Krishnan, Suba, McDonald, Dan, Maurer, Matthew, Gu, Xuemin, Neely, Jaclyn, Suryawanshi, Satyendra, Levy, Ronald, Khushalani, Nikhil, Wu, Jennifer, Zhang, Jinyu, Basher, Fahmin, Rubinstein, Mark, Bucsek, Mark, and Qiao, Guanxi

Subjects
Good Health and Well Being
Published
2016

50. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

Author

Luis Felipe Campesato, Sadna Budhu, Jeremy Tchaicha, Chien-Huan Weng, Mathieu Gigoux, Ivan Jose Cohen, David Redmond, Levi Mangarin, Stephane Pourpe, Cailian Liu, Roberta Zappasodi, Dmitriy Zamarin, Jill Cavanaugh, Alfredo C. Castro, Mark G. Manfredi, Karen McGovern, Taha Merghoub, and Jedd D. Wolchok

Subjects
Science
Abstract

The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.

Published
2020
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