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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE280640 | GEO | 2025/02/27

REPOSITORIES: GEO

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

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Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters

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Project description:Age-associated microglial dysfunction contributes to the accumulation of amyloid-b (Ab) plaques in Alzheimer’s disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer’s disease. Here we found that naturally aged microglia phagocytosed less Ab over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Ab. Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Ab phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Ab uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Ab phagocytosis that likely underlies the progression to neurologic disease.

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