Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2⁺ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8⁺ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8⁺ TIL infiltration and effector function. TREM2⁺ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.

将检查点抑制剂 (CPI) 耐药个体转变为有反应需要确定抑制机制。我们在小鼠同系肿瘤模型和多种组织学类型的人类实体瘤中确定 TREM2 ⁺肿瘤相关巨噬细胞 (TAM) 与耗尽的 CD8 ⁺肿瘤浸润淋巴细胞 (TIL) 相关。 Fc 结构域增强的抗 TREM2 单克隆抗体 (mAb) 疗法通过消除和调节 TAM 群体来促进抗肿瘤免疫，从而增强 CD8 ⁺ TIL 浸润和效应器功能。 TREM2 ⁺ TAM 在卵巢癌个体中最为丰富，其中 TREM2 表达与疾病分级相对应，且无复发生存率较差。在侵袭性原位卵巢癌模型中，抗 TREM2 mAb 疗法可驱动有效的抗肿瘤免疫。这些结果凸显了 TREM2 作为免疫治疗调节的一个极具吸引力的靶标，适用于对 CPI 治疗难治且可能具有富含 TAM 的肿瘤微环境的个体。