Abstract 6823: The role of aging in immune mediated reactivation from metastatic dormancy

Abstract Age is the strongest prognostic risk factor for melanoma-related death, and metastasis remains the primary driver of mortality. Yet despite this clear link, the mechanistic basis for why melanoma progression and metastatic outgrowth disproportionately worsen in older adults (65 years) remains poorly understood. A key gap lies in the field’s reliance on young (∼8-week-old, equivalent to 20 human years) mouse models, which fail to capture the age-related dynamics such as immune dysfunction that shape metastatic behavior. Moreover, most studies have focused exclusively on lung metastasis, despite melanoma commonly metastasizing to sites such as the liver, which are more resistant to immune checkpoint inhibitors. To address these limitations, we developed novel syngeneic models of melanoma metastasis and colonization in young (8 weeks), middle-aged (12-16 months), and geriatric (22-26 months) mice, targeting metastases specifically to the lung or liver. Strikingly, both lung and liver metastases were increased in middle-aged mice, whereas young and geriatric mice showed limited outgrowth, recapitulating human data where melanoma incidence is low in young adults (50 years), peaks between ages 65-79, and decreases thereafter (79+). These aging mouse models allow us, for the first time, to systematically assess immune surveillance pathways associated with age-induced melanoma reactivation (middle-aged) and dormancy (young and geriatric). Of the various immune subsets profiled, we found that γδ T-cells are decreased in the lungs and livers of middle-aged mice with metastatic disease but are elevated in young and (surprisingly) geriatric mice. Depletion of γδ T-cells in both young and geriatric mice reawakened dormant melanoma cells and promoted aggressive metastasis. We next assessed cytokine-specific changes in the pre-metastatic lung and liver that might explain this altered γδ T-cell phenotype. We found the cytokine ARG1 was markedly increased by CD11b+ myeloid cells in the middle-aged lung and liver only. r-ARG1 treatment in young mice was sufficient to induce metastatic reactivation, reduce γδ T-cell abundance, promote γδ T-cell exhaustion, and also reduced human Vγ9Vδ2 T-cell killing of human melanoma cells ex-vivo. Finally, in vivo treatment with the ARG1 inhibitor CB-1158 reduced metastatic outgrowth in both the lung and liver of middle-aged mice, with no effect in young or geriatric hosts. Treatment was associated with increased γδ T-cell abundance, enhanced activation, and reduced exhaustion within the metastatic TME of middle-aged mice. These findings uncover a previously unrecognized age-specific ARG1-γδ T-cell immunoregulatory axis that drives melanoma reactivation and metastatic progression selectively in middle-aged hosts. This work underscores the critical need for age-appropriate modeling and identifies ARG1 and γδ T-cells as a promising therapeutic target in elderly melanoma patients. Citation Format: Mitchell Fane, Kelly Coutant, Jhon Pasamonte, Pulkit Datt, Anastasia. The role of aging in immune mediated reactivation from metastatic dormancy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6823.