The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice^1,2,3,4,5,6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma^7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2–RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2–RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2–RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.

肠道菌群是免疫检查点抑制剂治疗期间抗肿瘤免疫的重要调节因子。已在小鼠中鉴定出几种促进对免疫检查点抑制剂的抗肿瘤反应的细菌^1,2,3,4,5,6。此外，移植反应者的粪便标本可以提高黑色素瘤患者抗 PD-1 治疗的疗效^7,8。然而，粪便移植增加的疗效是可变的，肠道细菌如何促进抗肿瘤免疫仍不清楚。在这里，我们表明肠道微生物组下调 PD-L2 表达及其结合伴侣排斥引导分子 b （RGMb） 以促进抗肿瘤免疫并鉴定介导这种作用的细菌种类。PD-L1 和 PD-L2 作为结合伴侣共享 PD-1，但 PD-L2 也可以结合 RGMb。我们证明，阻断 PD-L2-RGMb 相互作用可以克服微生物组对 PD-1 通路抑制剂的耐药性。抗体介导的 PD-L2-RGMb 通路阻断或 T 细胞中 RGMb 的条件性缺失与抗 PD-1 或抗 PD-L1 抗体联合使用可促进多种小鼠肿瘤模型中的抗肿瘤反应，这些小鼠肿瘤模型对单独抗 PD-1 或抗 PD-L1 没有反应（无菌小鼠、抗生素处理的小鼠，甚至用对治疗无反应的患者的粪便样本定植的小鼠）。这些研究将 PD-L2-RGMb 通路的下调确定为肠道微生物群可以促进对 PD-1 检查点阻断反应的特定机制。结果还确定了一种可能有效的免疫策略，用于治疗对 PD-1 癌症免疫治疗无反应的患者。