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

Siwakorn Punyawatthananukool, Ryuma Matsuura, Thamrong Wongchang, Nao Katsurada, Tatsuaki Tsuruyama, Masaki Tajima, Yutaka Enomoto, Toshio Kitamura, Masahiro Kawashima, Masakazu Toi, Koji Yamanoi, Junzo Hamanishi, Shigeo Hisamori, Kazutaka Obama, Varodom Charoensawan, Dean Thumkeo and Shuh Narumiya ()
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Siwakorn Punyawatthananukool: Kyoto University Graduate School of Medicine
Ryuma Matsuura: Kyoto University Graduate School of Medicine
Thamrong Wongchang: Kyoto University Graduate School of Medicine
Nao Katsurada: Kyoto University Graduate School of Medicine
Tatsuaki Tsuruyama: Kyoto University Graduate School of Medicine
Masaki Tajima: Kyoto University Graduate School of Medicine
Yutaka Enomoto: The University of Tokyo
Toshio Kitamura: The University of Tokyo
Masahiro Kawashima: Kyoto University Graduate School of Medicine
Masakazu Toi: Kyoto University Graduate School of Medicine
Koji Yamanoi: Kyoto University Graduate School of Medicine
Junzo Hamanishi: Kyoto University Graduate School of Medicine
Shigeo Hisamori: Kyoto University Graduate School of Medicine
Kazutaka Obama: Kyoto University Graduate School of Medicine
Varodom Charoensawan: Mahidol University
Dean Thumkeo: Kyoto University Graduate School of Medicine
Shuh Narumiya: Kyoto University Graduate School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation, and PGE2 blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE2-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.

Date: 2024
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DOI: 10.1038/s41467-024-53706-3

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