Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2)
Spotlight (1) Markosyan N (2) Li J (3) Sun YH (4) Richman LP (5) Lin JH (6) Yan F (7) Quinones L (8) Sela Y (9) Yamazoe T (10) Gordon N (11) Tobias JW (12) Byrne KT (13) Rech AJ (14) FitzGerald GA (15) Stanger BZ (16) Vonderheide RH
Markosyan and Li et al. found that EPHA2 expression negatively correlated with CD8+ T cell infiltration in human and mouse pancreatic ductal adenocarcinoma (PDA). Murine EPHA2-/- tumors increased T cell infiltration, MHC-I and inflammatory gene expression and chemo- immunotherapy treatment sensitivity. PTGS2 was highly expressed in T cell-excluded PDA tumors and PTGS2-/- PDA had greater T cell numbers, reduced immune-suppressive markers, and extended mouse survival; overexpression had the opposite effects. PTGS2 appears to be regulated by EPHA2 via the TGFβ/SMAD3 axis, and inhibition improved treatment outcome.
Contributed by Alex Najibi
(1) Markosyan N (2) Li J (3) Sun YH (4) Richman LP (5) Lin JH (6) Yan F (7) Quinones L (8) Sela Y (9) Yamazoe T (10) Gordon N (11) Tobias JW (12) Byrne KT (13) Rech AJ (14) FitzGerald GA (15) Stanger BZ (16) Vonderheide RH
Markosyan and Li et al. found that EPHA2 expression negatively correlated with CD8+ T cell infiltration in human and mouse pancreatic ductal adenocarcinoma (PDA). Murine EPHA2-/- tumors increased T cell infiltration, MHC-I and inflammatory gene expression and chemo- immunotherapy treatment sensitivity. PTGS2 was highly expressed in T cell-excluded PDA tumors and PTGS2-/- PDA had greater T cell numbers, reduced immune-suppressive markers, and extended mouse survival; overexpression had the opposite effects. PTGS2 appears to be regulated by EPHA2 via the TGFβ/SMAD3 axis, and inhibition improved treatment outcome.
Contributed by Alex Najibi
Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted 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 EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGFbeta 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 novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGFbeta-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.
Author Info: (1) Department of Medicine. (2) Abramson Family Cancer Research Institute. (3) Center for RNA Biology, Department of Biochemistry and Biophysics, Department of Urology, University
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Author Info: (1) Department of Medicine. (2) Abramson Family Cancer Research Institute. (3) Center for RNA Biology, Department of Biochemistry and Biophysics, Department of Urology, University of Rochester Medical Center, Rochester, New York, USA. (4) Abramson Family Cancer Research Institute. (5) Abramson Family Cancer Research Institute. (6) Abramson Family Cancer Research Institute. (7) Abramson Family Cancer Research Institute. (8) Abramson Family Cancer Research Institute. (9) Abramson Family Cancer Research Institute. (10) Abramson Family Cancer Research Institute. (11) Penn Genomic Analysis Core. (12) Department of Medicine. Parker Institute for Cancer Immunotherapy. (13) Abramson Family Cancer Research Institute. Parker Institute for Cancer Immunotherapy. (14) Department of Systems Pharmacology and Translational Therapeutics. Institute for Translational Medicine and Therapeutics. (15) Department of Medicine. Abramson Family Cancer Research Institute. Parker Institute for Cancer Immunotherapy. Department of Cell and Developmental Biology. Abramson Cancer Center, and. (16) Department of Medicine. Abramson Family Cancer Research Institute. Parker Institute for Cancer Immunotherapy. Abramson Cancer Center, and. Institute for Immunology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Citation: J Clin Invest 2019 Jun 4 130: Epub06/04/2019