Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer’s disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2^–/– mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1⁺ and CX₃CR1⁺ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.

检查点免疫疗法释放 T 细胞对肿瘤的控制，但被免疫抑制性骨髓细胞破坏。TREM2 是一种髓样受体，可在阿尔茨海默病期间传输维持小胶质细胞反应的细胞内信号。TREM2 也由肿瘤浸润巨噬细胞表达。在这里，我们发现Trem2 ^–/–小鼠比野生型小鼠更能抵抗各种癌症的生长，并且对抗 PD-1 免疫疗法的反应更灵敏。此外，当与抗 PD-1 联合使用时，抗 TREM2 mAb 治疗可抑制肿瘤生长并促进消退。scRNA-seq 显示 TREM2 缺失和抗 TREM2 都与缺乏 MRC1 ⁺和 CX ₃ CR1 ^{+ 相关}肿瘤中的巨噬细胞浸润，伴随着骨髓亚群的扩张，这些亚群表达了促进 T 细胞反应改善的免疫刺激分子。TREM2 在超过 200 例人类癌症病例的肿瘤巨噬细胞中表达，并且与两种癌症的延长生存期呈负相关。因此，TREM2 可能被靶向修饰肿瘤髓系浸润并增强检查点免疫治疗。