Blocking EP4 downregulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model

Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) pathway, is produced by tumors and surrounding stromal cells. It stimulates tumor progression, promotes angiogenesis, and suppresses the antitumor response. Pharmacological inhibition of PGE2 synthesis has been shown to suppress tumor initiation and growth in vivo. In the current study, we demonstrated that the growth of the Ptgs2-deficient the 3LL lung adenocarcinoma cell line was downregulated in vivo through natural killer (NK) cell activation and a reduction in the population of polymorphonuclear leukocyte-myeloid-derived suppressor cells (PMN-MDSCs) and tumor associated macrophages (TAMs). Based on these results, the therapeutic effect of ONO-AE3–208 (EP4i), an inhibitor of EP4 (a PGE2 receptor), combined with anti-PD-1Ab was evaluated. EP4i, but not anti-PD-1 Ab, decreased tumor metabolism including glycolysis, fatty acid oxidation, and oxidative phosphorylation. EP4i induced IFNγ production from only NK cells (not from T cells) and a shift from M2- to M1-like macrophages in TAMs. These effects were further enhanced by anti-PD-1 Ab treatment. Although CD8T cell infiltration was increased, IFNγ production was not significantly altered, even with combination therapy. Tumor hypoxia was ameliorated by either EP4i or anti-PD-1 Ab treatment, which was further affected by the combination. Normalization of tumor vessels was significant only for the combination therapy. The results indicate a novel effect of EP4i for the metabolic reprogramming of tumors, revealed unique features of EP4i that can synergize with anti-PD-1Ab to promote IFNγ production of NK cells, polarize TAMs into the M1-phenotype, and reduce hypoxia through normalization of the tumor vasculature.

This is a pre-copyedited, author-produced version of an article accepted for publication in International Immunology following peer review. The version of record [Miho Tokumasu, Mikako Nishida, Takamasa Kawaguchi, Ikuru Kudo, Tohru Kotani, Kazuhiko Takeda, Takao Yoshida, Heiichiro Udono, Blocking EP4 downregulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model, International Immunology, 2022;, dxac004, https://doi.org/10.1093/intimm/dxac004] is available online at: https://doi.org/10.1093/intimm/dxac004