Abstract A083: A Prostaglandin E2 receptor 2/4 (EP2/4) dual antagonist, OCT-598, enhances the response to conventional chemotherapy in gastric cancer through restoring tumor immunity

Abstract Palliative first-line therapy for patients with unresectable or metastatic gastric cancer typically involves 5-fluorouracil (5-FU) and platinum-based drug. However, patients with advanced gastric cancer often have poor prognosis. It is well established that chemotherapeutic agents increase the expression of cycloocygenase-2 (COX-2) in cancer cells, which in turn increase prostaglandin E2 (PGE2) production in the tumor microenvrionment. PGE2 binds to prostaglandin receptors (EP1-4) on immune cells, contributing to the establishment of an immunosuppressive miroenvironment. Chemotherapy-induced PGE2 may contcontribute to therapy resistance. Murine gastric cancer cell lines, YTN3 and YTN16, were treated with 5-FU and oxaliplatin for 24 hours. COX-2 gene expression (Ptgs2, prostaglandin-endoperoxide synthase 2) was assessed using quantitative reverstranscriptase polymerase chain reaction (qRT-PCR), and PGE2 levels in conditioned media were measured using ELISA. Recombinant PGE2 was treated to macrophage (RAW264.7) and T lymphocyte (EL4) for 48 hours. The gene exrpression of immune-suppressive markers, Il10 and Arg1, and T cell activation markers, Gzmb, Ifng, and Il2, were evaluated using qRT-PCR. YTN3 cells were subcutaneously injected into C57BL/6J mice. Chemotherapeutic agents and vehicle controls were injected intraperitoneally twice a week OCT-598 and vehicle were administrated orally every day. Tumor infiltrated immune cells were assessed by flow cytometry. Combination chemotherapy of 5-FU and oxaliplatin increased Ptgs2 expression and PGE2 production in YTN3 and YTN16 cells. PGE2 upregulated immune-suppressive marker expression in RAW264.7 cells and decreased T cell activation marker genes expression in EL4 cells. Futhermore, the EP2/4 dual antagonist OCT-598 reversed the immunosuppressive effect of PGE2. In vivo, chemotherapy alonen did not significantly attenuate tumor growth but increased PGE2 level in tumor tissues. The triple combination therapy of 5-FU, oxaliplatin, and OCT-598 induced significant tumor regression, whereas OCT-598 monotherpay did not affect tumor growth. After one week of treatment, tumor-infiltrated immune cell populaitons were evalulated. The proportion of M2 macgrophages (CD45+F4/80+CD206+) to M0 macorphage (CD45+F4/80+) decreased, while the proportion of CD4+ T cells (CD45+TCRβ+CD4+) to total T cells (CD45+TCRβ+) increased in the triple combination group. Conventional chemotherapy induces COX-2 (Ptgs2) expression and subsequent PGE2 production., contributing to the formation immunosuppressive tumor microenvironment. The EP2/4 dual antagonist, OCT-598, restores tumor immunity and overcomes chemotherapy ressistance. Citation Format: Dagyeong Lee, Hye Jeong Oh, Yulim Lee, Han Na Oh, Hoon Hur. A Prostaglandin E2 receptor 2/4 (EP2/4) dual antagonist, OCT-598, enhances the response to conventional chemotherapy in gastric cancer through restoring tumor immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A083.