Abstract 4985: Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing anti-tumor immunity

Abstract

Abstract Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME). Using a genetically engineered mouse model of pancreatic ductal adenocarcinoma, we demonstrate that deleting the terminal PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through cognate EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME to activate T cell immunity and suppress tumor growth. Knockout (KO) of Ptges (the gene encoding PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D/P53R172H/Yfp/CrePd) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner (KO vs control p<0.0001 for both). Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges and Ptger4 KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4 KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected role for autocrine mPGES1-PGE2-EP4 signaling axis in pancreatic cancer cells, nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing approaches in cancer therapy. Citation Format: Nune Markosyan, Ilkyu Kim, Charu Arora, Noah Cheng, Emma Schechter, John Tobias, Ben Stanger, Robert Vonderheide. Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4985.