Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)
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
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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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 8

Pharmacological inhibition of PTGS2 sensitizes PDA to immunotherapy.

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Pharmacological inhibition of PTGS2 sensitizes PDA to immunotherapy. (A)...
(A) Changes in tumor volume 27 days after treatment start, relative to the baseline. KPC tumor cells were implanted subcutaneously in WT mice. IgG, X, P, F, and XPF treatments started 18 days after tumor implantation. Each column represents a single mouse (n = 8–10/group). (B) Growth curves of subcutaneously implanted KPC tumors in WT mice (n = 10/group). IgG, X, or XPF treatments started 18 days after implantation (black arrow). (C) Overall survival of KPCY mice without treatment and with XPF treatment started in mice with tumor volume of less than 20 mm3 (n = 11–36/group). (D) Schematic representation of EPHA2/TGF-β/SMAD/PTGS2 axis in PDA TME. Statistical analysis of tumor growth curves performed using linear mixed-effects model with Tukey’s HSD post test using the lme4 (B). The log-rank P values for Kaplan-Meier curves in C were calculated in GraphPad Prism. *P < 0.05.