Age-associated modulation of TREM1/TREM2 expressing macrophages promotes melanoma progression and metastasis

Aging is a known risk factor for melanoma, yet the mechanisms underlying melanoma progression and metastasis in the older population remain largely unexplored. Among remaining gaps is the role of changes in melanoma microenvironment in key phenotypes exacerbated by age. Here we demonstrate that age enriches immunosuppressor tumor microenvironment which can be linked with melanoma metastasis phenotype. Age-associated macrophages with a tolerogenic phenotype and dysfunctional CD8 positive cells with an exhausted phenotype were identified in melanomas of aged mice and human. Macrophages of the older population were enriched of the immunosuppressor subcluster expressing Trem2 while the profibrotic subcluster expressing Trem1 was reduced. Notably, inhibition of TREM1 decreased melanoma growth in young but not old mice, whereas inhibition of TREM2 prevented lung metastasis in aged mice. These data identify novel targets in melanoma metastasis which may guide aged-dependent immunotherapies. Single cell gene expression analysis of melanoma Cd45 cells in 4-, 12-, and 20-months old mice using PIP-seq