Abstract A019: Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells infiltrating human tumor

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Abstract PGE2 is a predominant lipid mediator in the tumor microenvironment, synthesized by the action of the cyclooxygenase (COX). In mice, inhibiting PGE2 signaling suppresses tumor progression. In humans, daily use of COX inhibitors, such as aspirin and NSAIDs, reduces cancer initiation and mortality. While numerous immunosuppressive mechanisms of PGE2 have been suggested, most are based on animal models, leaving PGE2-mediated immunosuppressive mechanisms in human cancer largely unknown. In this study, we used comparative single-cell RNA-sequencing of human and syngeneic mouse tumors to dissect the function of PGE2 . We found in CD8+ T cells that high expression of PGE receptor EP4 and to a lesser extent EP2, is associated with downregulation of IL-2-STAT5 signaling, oxidative phosphorylation (OXPHOS), glycolysis, as well as MYC target genes such as ribosomal proteins (RPs). A similar downregulation of OXPHOS, glycolysis, and RP gene expression was also found in infiltrating myeloid cells. Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation. In activated CD8+ T cells, PGE2-EP2/EP4 signaling blocks IL-2-STAT5 signaling by downregulation of Il2ra, which in turn downregulates c-Myc and PGC-1, leading to decreased OXPHOS, glycolysis, and ribosome biogenesis. This results in reduced migration activity, poor survival and expansion capacity, and consequently impaired anti-tumor immunity. Similarly, EP4 and EP2 are induced upon activation in macrophages, and PGE2 downregulates Myc pathway and OXPHOS in these cells in M0 and M1 states. These results suggest that PGE2 impairs both adaptive and innate immunity in the tumor microenvironment by hampering their bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells via EP4 and EP2 receptors. Citation Format: Siwakorn Punyawatthananukool, Ryuma Matsuura, Thamrong Wongchang, Nao Katsurada, Tatsuaki Tsuruyama, Masaki Tajima, Yutaka Enomoto, Toshio Kitamura, Masahiro Kawashima, Masakazu Toi, Koji Yamanoi, Jyunzo Hamanishi, Shigeo Hisamori, Kazutaka Obama, Varodom Charoensawan, Dean Thumkeo, Shuh Narumiya. Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells infiltrating human tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A019.

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