Blocking EP4 down-regulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model.
Blocking EP4 down-regulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model.
复制标题
阻断 EP4 可下调肿瘤代谢，并与抗 PD-1 疗法协同作用，激活肺腺癌模型中的自然杀伤细胞。
DOI：
10.1093/intimm/dxac004
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发表时间：
2022
影响因子：
4.4
通讯作者：
Udono H.
中科院分区：
文献类型：
--
作者：
Tokumasu M;Nishida M;Kawaguchi T;Kudo I;Kotani T;Takeda K;Yoshida T;Udono H.
前列腺素 E2 (PGE2) 是环氧合酶 (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。 PGE2 合成的药理学抑制已被证明可以抑制体内肿瘤的发生和生长。在当前的研究中，我们证明了Ptgs2缺陷的3LL肺腺癌细胞系的生长在体内通过自然杀伤（NK）细胞激活以及多形核白细胞-骨髓源性抑制细胞（PMN-MDSC）和肿瘤相关巨噬细胞（TAM）数量的减少而下调。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 仅诱导 NK 细胞（而非 T 细胞）产生 IFNγ，并诱导 TAM 巨噬细胞从 M2 样巨噬细胞转变为 M1 样巨噬细胞。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，但即使采用联合治疗，IFNγ 的产生也没有显着改变。 EP4i 或抗 PD-1 抗体治疗可改善肿瘤缺氧，联合用药可进一步改善肿瘤缺氧。肿瘤血管的正常化仅对联合治疗有意义。结果表明 EP4i 对肿瘤代谢重编程具有新的作用，并揭示了 EP4i 的独特功能，可以与抗 PD-1 抗体协同促进 NK 细胞产生 IFNγ，将 TAM 极化为 M1 表型，并通过肿瘤血管正常化减少缺氧。
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 growthin vivo. In the current study, we demonstrated that the growth of the Ptgs2-deficient 3LL lung adenocarcinoma cell line was down-regulatedin vivothrough 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.