The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4 + T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.

中文翻译：

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TREM2 缺陷重新编程肠道巨噬细胞和微生物群以增强抗 PD-1 肿瘤免疫治疗


肠道微生物群和肿瘤相关巨噬细胞 (TAM) 影响肿瘤对抗程序性细胞死亡蛋白 1 (PD-1) 免疫检查点阻断的反应。通过阻断或删除骨髓细胞上的巨噬细胞受体触发受体 2 (TREM2) 来重新编程 TAM 可减弱肿瘤生长，而功能性 TREM2 的缺乏可增强抗 PD-1 消除肿瘤的作用。在这里，我们发现抗 PD-1 治疗与小鼠 TREM2 缺陷相结合会诱导肠道巨噬细胞的促炎程序，并伴随肠道微生物群中的瘤胃球菌的扩张。对野生型小鼠灌胃 R. gnavus 增强了抗 PD-1 介导的肿瘤消除，重现了在不存在 TREM2 的情况下发生的效果。促炎肠道环境与产生 TNF 的 CD4 + T 细胞扩张、循环增加和迁移至肿瘤床同时发生。因此，TREM2 通过调节肠道免疫环境和微生物群来远程控制抗 PD-1 免疫检查点阻断，R. gnavus 成为一种潜在的益生菌剂，可提高抗 PD-1 的反应性。