Targeting TREM2 on tumor-associated macrophages enhances immunotherapy

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. [Display omitted] •TAM-expressed TREM2 is associated with T cell exhaustion and anti-PD-1 resistance•Effector-enhanced anti-TREM2 antibody treatment drives anti-tumor immunity•TAM abundance and suppression are reduced following anti-TREM2 therapy•Anti-TREM2 therapy potentiates T cell activation and response to anti-PD-1 treatment Binnewies et al. show that TREM2-expressing tumor-associated macrophages (TAMs) are critical mediators of immune suppression in the tumor microenvironment (TME) and correlate with T cell exhaustion in human cancer. Effector-enhanced anti-TREM2 antibody treatment alters the abundance and phenotype of TAMs in the TME and sensitizes the response to anti-PD-1 therapy.