Inosine modulates antitumor immunity Checkpoint blockade immunotherapy harnesses the immune system to kill cancer cells and has been used with great success to treat certain tumors, but not all cancer patients respond. The efficacy of checkpoint blockade immunotherapy has been shown to depend on the presence of distinct, beneficial bacteria residing in the gut of patients, but how the microbiome mediates such beneficial effects is unclear. Mager et al. found that specific bacteria produce a metabolite called inosine that enhances the effect of checkpoint blockade immunotherapy (see the Perspective by Shaikh and Sears). In mouse models, inosine, together with proinflammatory stimuli and immunotherapy, strongly enhanced the antitumor capacities of T cells in multiple tumor types, including colorectal cancer, bladder cancer, and melanoma. Science, this issue p. 1481; see also p. 1427 The bacterial-derived metabolite inosine enhances cancer immunotherapy in mice. 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.

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微生物组衍生的肌苷调节对检查点抑制剂免疫疗法的反应

肌苷调节抗肿瘤免疫检查点阻断免疫疗法利用免疫系统杀死癌细胞，并已成功用于治疗某些肿瘤，但并非所有癌症患者都有反应。检查点阻断免疫疗法的功效已被证明取决于患者肠道中是否存在独特的有益细菌，但微生物组如何介导这种有益作用尚不清楚。马格等人。发现特定细菌会产生一种称为肌苷的代谢物，可增强检查点阻断免疫疗法的效果（参见 Shaikh 和 Sears 的观​​点）。在小鼠模型中，肌苷与促炎刺激和免疫疗法一起，强烈增强了 T 细胞在多种肿瘤类型中的抗肿瘤能力，包括结直肠癌、膀胱癌和黑色素瘤。科学，这个问题 第1481章 另见第 1427 细菌衍生的代谢物肌苷可增强小鼠的癌症免疫治疗。几种肠道细菌与检查点阻断免疫疗法的疗效增强有关，但微生物组增强抗肿瘤免疫的潜在机制尚不清楚。在这项研究中，我们分离了三种细菌——假长双歧杆菌、约氏乳杆菌和奥尔森氏菌——它们在四种癌症小鼠模型中显着增强了免疫检查点抑制剂的功效。我们发现肠道假长双歧杆菌通过产生代谢物肌苷来调节增强的免疫治疗反应。免疫疗法诱导的肠道屏障功能下降增加了肌苷和活化的抗肿瘤 T 细胞的全身易位。肌苷的作用取决于腺苷 A2A 受体的 T 细胞表达和所需的共刺激。总的来说，我们的研究确定了一种以前未知的由免疫疗法激活的微生物代谢物免疫途径，可用于开发基于微生物的辅助疗法。