Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Research Center of Oncology, Ono Pharmaceutical, Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
Int Immunol. 2022 Jun 4;34(6):293-302. doi: 10.1093/intimm/dxac004.
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.
前列腺素 E2（PGE2）是环氧化酶（COX）途径的产物，由肿瘤和周围基质细胞产生。它刺激肿瘤进展，促进血管生成并抑制抗肿瘤反应。已表明抑制 PGE2 合成的药理学抑制作用可抑制体内肿瘤的起始和生长。在本研究中，我们通过自然杀伤（NK）细胞激活和减少多形核白细胞-髓样来源的抑制细胞（PMN-MDSC）和肿瘤相关巨噬细胞（TAM）的数量，证明了 Ptgs2 缺陷的 3LL 肺腺癌细胞系的生长在体内受到下调。基于这些结果，评估了 EP4（PGE2 受体）抑制剂 ONO-AE3-208（EP4i）与抗 PD-1 抗体联合的治疗效果。EP4i（而非抗 PD-1 抗体）降低了肿瘤代谢，包括糖酵解、脂肪酸氧化和氧化磷酸化。EP4i 仅从 NK 细胞（而非 T 细胞）诱导 IFNγ产生，并使 TAMs 中的 M2 样巨噬细胞向 M1 样巨噬细胞转变。抗 PD-1 抗体治疗进一步增强了这些作用。尽管 CD8 T 细胞浸润增加，但 IFNγ产生并未明显改变，即使联合治疗也是如此。EP4i 或抗 PD-1 抗体治疗改善了肿瘤缺氧，联合治疗进一步影响了肿瘤缺氧。仅联合治疗可显著改善肿瘤血管正常化。结果表明 EP4i 具有肿瘤代谢重编程的新作用，并揭示了 EP4i 的独特特征，可与抗 PD-1 抗体协同作用，促进 NK 细胞产生 IFNγ，将 TAMs 极化为 M1 表型，并通过肿瘤血管正常化减轻缺氧。
