TREM2 Sensing of Tumor Cell Efferocytosis Promotes a Macrophage Molecular State that Limits NK Cell Antitumor Immunity

Macrophages (MΦ) form a highly heterogenous compartment within tumor lesions.  Using lineage tracing, we recently established that advanced NSCLC lesions in both mice and humans are depleted of tissue-resident macrophages (TRM) and are mainly populated by monocyte-derived MΦ (MoMΦ). Here, we show that TREM2+ MoMΦ dominate murine and human NSCLC lesions. Importantly, using mice reconstituted with mixed TREM2-deficient and -proficient bone marrow cells, we identified a cell-intrinsic ability for TREM2 to drive an efferocytosis-associated molecular program that profoundly reduced the expression of immunogenic molecules in tumor-infiltrating MoMΦ. Trem2 deletion significantly dampened this program, reversed MoMΦ immunosuppression, and significantly enhanced the accumulation of activated NK cells and cDC1 in tumor lesions. Notably, Trem2 deletion reduced lung cancer progression in an NK cell-dependent manner. Taken together, our results underscore the potential for therapeutic inhibition of TREM2 to mount a potent anti-tumor immune response by unleashing cooperative NK/cDC1 cell function.