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Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)
Nune Markosyan, … , Ben Z. Stanger, Robert H. Vonderheide
Nune Markosyan, … , Ben Z. Stanger, Robert H. Vonderheide
Published June 4, 2019
Citation Information: J Clin Invest. 2019;129(9):3594-3609. https://doi.org/10.1172/JCI127755.
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Research Article Immunology Oncology

Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)

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Abstract

Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell–inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGF-β and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-β/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.

Authors

Nune Markosyan, Jinyang Li, Yu H. Sun, Lee P. Richman, Jeffrey H. Lin, Fangxue Yan, Liz Quinones, Yogev Sela, Taiji Yamazoe, Naomi Gordon, John W. Tobias, Katelyn T. Byrne, Andrew J. Rech, Garret A. FitzGerald, Ben Z. Stanger, Robert H. Vonderheide

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Figure 3

Tumor cell–intrinsic Epha2 regulates sensitivity to immunotherapy.

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Tumor cell–intrinsic Epha2 regulates sensitivity to immunotherapy.
(A an...
(A and B) Epha2-WT and Epha2-KO tumor growth and mouse survival with or without the GAFCP treatment. Tumor cells implanted subcutaneously into C57BL/6 mice (n = 4–8/group). GAFCP treatment started 12 days after implantation, at 3–5 mm tumor diameter. (C) Size change of Epha2-WT and Epha2-KO tumors from indicated clones relative to the baseline after 3 weeks with or without GAFCP treatment. PDA tumor cells were implanted subcutaneously into C57BL/6 mice (n = 4–8/group) and treated with GAFCP for 12 days (average tumor diameter 3–5 mm at the treatment start). Statistical differences between groups calculated by linear mixed-effects model with Tukey’s HSD post test using the lme4 in R (A and B, left). The log-rank P values for Kaplan-Meier survival curves were calculated in GraphPad Prism (A and B, right). ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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