Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d'Immunomonitoring en Oncologie, F-94805, Villejuif, France.
Université Paris-Saclay, Faculté de Médicine, Le Kremlin Bicêtre, F-94276, France.
Nat Commun. 2020 May 1;11(1):2168. doi: 10.1038/s41467-020-16079-x.
Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
肠道微生物组成影响晚期癌症患者免疫检查点的临床获益，但这种关系的潜在机制尚不清楚。肠道微生物影响免疫反应的分子机制主要归因于肠道微生物代谢物。短链脂肪酸（SCFA）通过细菌对膳食纤维的发酵在结肠中大量产生。我们在接受抗 CTLA-4 阻断 mAb 治疗的小鼠和患者中评估了 SCFA 水平是否与临床结果相关。高血液丁酸盐和丙酸盐水平与 CTLA-4 阻断的耐药性以及 Treg 细胞的比例较高有关。在小鼠中，丁酸盐抑制抗 CTLA-4 诱导的树突状细胞上 CD80/CD86 和 T 细胞上 ICOS 的上调、肿瘤特异性 T 细胞和记忆 T 细胞的积累。在患者中，高血液丁酸盐水平适度调节 ipilimumab 诱导的记忆和 ICOS+CD4+T 细胞和 IL-2 浸渍。总之，这些结果表明 SCFA 限制了抗 CTLA-4 活性。
