Age-Associated Modulation of TREM1/2-Expressing Macrophages Promotes Melanoma Progression and Metastasis

Aging is a known risk factor for melanoma, yet mechanisms underlying melanoma progression and metastasis in older populations remain largely unexplored. Aging might alter phenotypes of cells in the melanoma microenvironment, selecting for populations that support metastatic progression. In this study, we have demonstrated that age engenders the development of an immunosuppressive tumor microenvironment, which is linked to phenotypes associated with melanoma metastasis. Among cellular populations enriched by aging were macrophages with a tolerogenic phenotype expressing TREM2 and dysfunctional CD8+ T cells with an exhausted phenotype, whereas macrophages with a profibrotic phenotype expressing TREM1 were depleted. Notably, TREM1 inhibition decreased melanoma growth in young but not in old mice, whereas TREM2 inhibition prevented lung metastasis in aged mice. These data identify age-related targets associated with melanoma metastasis and may guide age-dependent immunotherapeutic strategies. TREM2 is elevated in melanoma-associated macrophages of aged mice and humans and can be inhibited to block melanoma metastasis, highlighting the role of the microenvironment in promoting aging-related metastasis.