Abstract B33: Tumor cell-intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2) in pancreatic adenocarcinoma
Authors: Markosyan Nune , Li Jinyang , Sun Yu , Richman Lee , Lin Jeffrey , Yan Fangxue , Quinones Liz , Sela Yogev , Yamazoe Taiji , Gordon Naomi , Tobias John , Byrne Katelyn , Rech Andrew , FitzGerald Garret , Stanger Ben , Vonderheide Robert 
Published: March 2020

Abstract
Pancreatic adenocarcinoma (PDA) is highly refractory to immunotherapy, a consequence of T-cell exclusion from the tumor microenvironment (TME). Based on a pathway analysis of human PDAs, we hypothesized that the receptor tyrosine kinase ephrin A2 (EPHA2) drives this immunosuppressive TME, as its expression negatively correlated with CD8A, CD3, PRF1, GZMB, and patient survival (EPHA2low/EPHA2high log rank hazard ratio 0.115, 95% CI of ratio 0.0315-0.416, TCGA dataset). Deletion of Epha2 in tumor cells increased T-cell influx, decreased the number of infiltrating myeloid suppressor cells, and sensitized tumors to therapy. Treatment of Epha2-deficient tumors with combination of chemo and immunotherapy resulted in suppressed tumor growth or tumor regression in up to 85% of cases. Examination of Epha2-dependent gene expression nominated Ptgs2 as a downstream mediator of T-cell exclusion. Like EPHA2, PTGS2 exhibited a negative correlation with intratumoral T cells, cytolytic activity, and patient survival (PTGS2low/PTGS2high log rank hazard ratio 0.152, 95% CI of ratio 0.054-0.430, TCGA dataset). KPCY mice (mutant KrasG12D (K), dominant negative p53R172H (P), Cre recombinase (C), YFP protein (Y)) deficient in pancreatic ductal cell Ptgs2 had significantly increased overall survival compared to Ptgs2 sufficient KPCY mice (Ptgs2def/Ptgs2suff log rank hazard ratio 0.5001, 95% CI of ratio 0.294-0.851). Ptgs2 deletion promoted T-cell influx in both autochthonous and implanted tumors. Inversely, overexpression of Ptgs2 decreased the number of tumor-infiltrating T cells, increased the proportion of suppressor myeloid cells, and conferred resistance to the combination therapy. Remarkably, pharmacologic inhibition of PTGS2 sensitized the tumors to immunotherapy, suppressing the growth of implanted tumors and increasing the survival of treated KPCY mice (median survival of untreated and treated mice 151 and 199 days, respectively; survival curve log rank p-value= 0.017). These studies suggest that a tumor cell-intrinsic EPHA2-PTGS2 signaling axis regulates the immune TME in PDA and suggests that a two-step approach targeting T-cell exclusion and exhaustion holds promise for this treatment-refractory disease.
Citation Format: Nune Markosyan, Jinyang Li, Yu Sun, Lee Richman, Jeffrey Lin, Fangxue Yan, Liz Quinones, Yogev Sela, Taiji Yamazoe, Naomi Gordon, John Tobias, Katelyn Byrne, Andrew Rech, Garret FitzGerald, Ben Stanger, Robert Vonderheide. Tumor cell-intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2) in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B33.