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

DOI PDF PDF 参考文献30件 オープンアクセス
  • Miho Tokumasu
    Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 , Japan
  • Mikako Nishida
    Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 , Japan
  • Takamasa Kawaguchi
    Research Center of Oncology, Ono Pharmaceutical, Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585 , Japan
  • Ikuru Kudo
    Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 , Japan
  • Tohru Kotani
    Research Center of Oncology, Ono Pharmaceutical, Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585 , Japan
  • Kazuhiko Takeda
    Research Center of Oncology, Ono Pharmaceutical, Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585 , Japan
  • Takao Yoshida
    Research Center of Oncology, Ono Pharmaceutical, Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585 , Japan
  • Heiichiro Udono
    Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 , Japan

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<jats:title>Abstract</jats:title> <jats:p>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 anti-tumor 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 3LL lung adenocarcinoma cell line was down-regulated 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). On the basis of these results, the therapeutic effect of ONO-AE3-208 (EP4i), an inhibitor of EP4 (a PGE2 receptor), combined with anti-PD-1 antibody was evaluated. EP4i, but not anti-PD-1 antibody, 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-like to M1-like macrophages in TAMs. These effects were further enhanced by anti-PD-1 antibody treatment. Although CD8 T-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 antibody treatment, which was further affected by the combination. Normalization of tumor vessels was significant only for the combination therapy. The results indicated a novel effect of EP4i for the metabolic reprogramming of tumors and revealed unique features of EP4i that can synergize with anti-PD-1 antibody to promote IFNγ production by NK cells, polarize TAMs into the M1 phenotype, and reduce hypoxia through normalization of the tumor vasculature.</jats:p>

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