研究新进展—肠道菌群或与肿瘤免疫治疗效果相关

2021-04-30

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在过去的十年里，免疫检查点封闭抗体的使用彻底改变了癌症治疗。CTLA-4和PD-1阻断抗体是转移性黑色素瘤患者最常用的免疫疗法之一，但许多患者使用后仍无反应，复发很常见。CTLA-4治疗仅在大约20%患者中有效。最近的研究结果表明，肠道菌群的组成与CTLA-4和PD-1抗体的抗肿瘤功效有关。

众所周知，肠道中的一些共生细菌群产生的代谢物在免疫反应的调节中起着关键作用。这些代谢物包括短链脂肪酸 (short-chain fatty acids ,SCFAs)，主要是乙酸酯(C2)、丙酸酯(C3)和丁酸酯(C4)。考虑到这一点，法国Villejuif的Gustave Roussy癌症研究所的Nathalie Chaput博士的研究小组假设CTLA-4抗体的抗肿瘤效果可能受到体内微生物产生的短链脂肪酸的影响。

为了验证这一假设，将丁酸盐通过饮用水给予荷瘤小鼠。这些小鼠还接受了CTLA-4抗体或其同种型对照的i.p .注射。令人惊讶的是，在三种不同的肿瘤模型(CT26、MC38和MCA101)中，添加丁酸盐消除了CTLA-4的抗肿瘤作用。进一步研究，作者发现丁酸盐阻断了CTLA-4抗体诱导的树突细胞成熟，这限制了树突细胞刺激T细胞的能力，从而限制了抗肿瘤免疫能力。该小组发现，用ipilimumab(anti CTLA-4)治疗者的血液中丁酸盐水平高的黑色素瘤患者减少了记忆T细胞的积累。

以上研究成果发布在Nature Communications文献 ” Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer” 中，该研究小组使用了BioXCell的InVivoPlus anti-mouse CLTA-4(Clone: 9D9)抗体, 揭示了微生物产生的短链脂肪酸对CTLA-4抗体抗肿瘤的效果抑制。

研究新进展—肠道菌群或与肿瘤免疫治疗效果相关

摘要：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 upregulation 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.

研究新进展—肠道菌群或与肿瘤免疫治疗效果相关