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)

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 6

Ptgs2 ablation in PDA tumor cells increases tumor antigenicity and decreases immunosuppressive potential of the tumor.

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Ptgs2 ablation in PDA tumor cells increases tumor antigenicity and decr...
(A) Individual (left) and average (right) weights of subcutaneously implanted control and Ptgs2-KO tumors 12 days after subcutaneous implantation. (B–E) Flow cytometric analysis of control and Ptgs2-KO tumors 12 to 13 days after subcutaneous implantation in WT mice. Representative experiments of 3 presented (n = 6–12/group). Gating strategies presented in Supplemental Table 5. Data presented as box plots, with horizontal lines and error bars indicating mean and range, respectively. Statistical analysis between 2 groups performed using Student’s unpaired t test in GraphPad Prism. *P < 0.05; **P < 0.01; ***P < 0.001.