Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy
Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy
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DOI：
10.1126/science.abc3421
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发表时间：
2020-09-18
期刊：
影响因子：
56.9
通讯作者：
McCoy, Kathy D.
中科院分区：
文献类型：
--
作者：
Mager, Lukas F.;Burkhard, Regula;McCoy, Kathy D.
几种肠道细菌与检查点阻断免疫疗法的功效增强有关，但微生物组增强抗肿瘤免疫力的潜在机制尚不清楚。在这项研究中，我们分离出三种细菌--假长双歧杆菌、约氏乳杆菌和奥尔森氏菌--它们显著增强了免疫检查点抑制剂在四种小鼠癌症模型中的疗效。我们发现肠道B。假长杆菌通过代谢产物肌苷的产生调节增强的免疫治疗应答。免疫治疗引起的肠道屏障功能下降增加了肌苷的全身易位和活化的抗肿瘤T细胞。肌苷的作用依赖于腺苷A2 A受体的T细胞表达，并需要共刺激。总的来说，我们的研究确定了一个以前未知的微生物代谢物免疫途径激活的免疫治疗，可用于开发基于微生物的辅助治疗。
Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.