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 7

Tumor cell–intrinsic Ptgs2 promotes T cell–low TME and resistance to immunotherapy in PDA.

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Tumor cell–intrinsic Ptgs2 promotes T cell–low TME and resistance to imm...
(A) Relative expression of Ptgs2 mRNA measured by qPCR in T cell–high PDA tumor cell clones transduced with either empty vector (EV) or pCDH-FHC vector carrying mouse Ptgs2 gene for overexpression (Ptgs2-OE). Representative data from n = 3 independent experiments. (B and C) Representative immunofluorescent staining images (B) and quantification (C) of CD3+ T cells in 2838c3-EV and 2838c3-Ptgs2-OE subcutaneous tumors (n = 5/group): CD3 (red), YFP (green), and DAPI (blue). Original magnification, ×20. (D–F) Flow cytometric analysis of subcutaneously implanted empty vector or Ptgs2-OE tumors from indicated clones (n = 5-7/group). (G) Parental and Ptgs2-OE T cell–high tumor growth and mouse survival with or without GAFCP treatment. Tumor cells implanted subcutaneously into C57BL/6 mice (n = 5–8/group). GAFCP treatment started 9 days after implantation at 3–5 mm tumor diameter. (A, C–F) Data are presented as boxplots, with horizontal lines and error bars indicating mean and range, respectively. Statistical analysis between 2 groups calculated using Student’s unpaired t test (C–F). The log-rank P values for Kaplan-Meier curves in G were calculated using GraphPad Prism. Statistical analysis of tumor growth curves performed using linear mixed-effects model with Tukey’s HSD post test using lme4 and the survival package in R (G). *P < 0.05; ***P < 0.001.