Abstract C016: Local and systemic impact of stromal senescence on melanoma response to immune checkpoint inhibition

Abstract Melanoma stands as the most dangerous type of skin cancer and 5th most commonly diagnosed cancer among new cases in the United States. Even with recent advancements in immune checkpoint inhibitors (ICIs), up to ∼70% of all recipients will not experience any significant benefit in progression free or overall survival. The ability to anticipate and understand resistance to ICIs has been exceptionally difficult due to shortcomings in the preclinical models used to study melanoma’s heterogeneous pathology. A potential barrier to therapeutic efficacy is cellular senescence that exists in the melanoma tumor microenvironment (TME). Cellular senescence is induced when various pressures push a cell to exit the cell cycle, enter growth arrest, and adopt a completely new molecular, secretory, and functional phenotype to facilitate the necessary repairs. In the acute setting, reversible cellular senescence can recruit immune cells that facilitate the necessary tissue repair and prevent tumor growth. However chronic exposure to pro-inflammatory factors secreted by senescent cells such as cytokines and proteases can be overwhelmingly negative through the promotion of tumorigenesis and therapeutic resistance. The intersection of these pro-tumorigenic mechanisms in melanoma has underscored the importance of using a comprehensive in vivo model system that incorporates stromal senescence into an immunocompetent murine model and relevant human mutational burdens that recapitulates patient profiles. To address this, our lab uses the Yale University Melanoma Model (YUMM) cell line that is syngeneic to INK-ATTAC mice that contain a cassette that regulates stromal senescence. This allows for the exploration of the immune response that patients experience after receiving ICI treatment in concert with senescent stromal cell burdens in the tumor microenvironment (TME). Mice bearing single cell clone YUMM tumors are treated with combination immune checkpoint inhibitors (aPD-1+aCTLA-4) to generate both responder and non-responder phenotypes. When senescent cells are cleared from the TME, the non-responder clone tumor is re-sensitized to immune checkpoint inhibition and significantly reduces the tumor size. Immunohistochemical analyses of the local TME shows a significant recovery of immune infiltration upon stromal senescent cell clearance in the non-responder clone, where CD8 and CD4 T cells are allowed to infiltrate exclusively with AP+ICI treatment. Systemic shifts in mice bearing non-responding, ICI treated tumors reveal significant correlations of conventional dendritic cell type 1 and 2 ratios in concert with increased senescent cell burden in the spleen that are recovered with stromal senescent cell clearance. Overall, this data reveals a local and systemic shift in immune cell populations of responder and non-responder phenotypes that may be shifted to improve tumor sensitivity to immune checkpoint inhibition via senolytic intervention. Citation Format: Giselle C. Burton Sojo, Marcel O. Schmidt, Dori Rosenstrauch, Anton Wellstein. Local and systemic impact of stromal senescence on melanoma response to immune checkpoint inhibition [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C016.