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

Abstract 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. Here, we 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, while macrophages with a profibrotic phenotype expressing TREM1 were depleted. Notably, TREM1 inhibition decreased melanoma growth in young but not old mice, whereas TREM2 inhibition prevented lung metastasis in aged mice. These data identify age-related targets associated with melanoma metastasis and may guide aged-dependent immunotherapeutic strategies.