Abstract B047: Stromal senescence and response to immune checkpoint inhibition in melanoma

Abstract Melanoma is the 8th most commonly diagnosed cancer in the United States, predominantly driven by exposure to UV radiation leading to an abundant oncogenic mutational burden. However, very few models incorporate these mechanisms in their representation of the disease significantly influencing treatment responses. To address this, our lab uses the Yale University Melanoma Model (YUMM) irradiated cell line that contains clinically represented mutations that are imperative to melanoma development. As a result, these cells are sensitive to combination immune checkpoint inhibition making them a superior system to study the immune response in melanoma over less representative lines such as B16. These cells are injected into a syngeneic in vivo murine system C57/Bl6 INK-ATTAC mice with a senescent cell depletion cassette exclusively expressed in the host stroma, incorporating cellular senescence as a key contributor to the host response to cancer. This dual system allows for the exploration of the immune response that patients experience after receiving ICI treatment in concert with senescent stromal cell burden in the tumor microenvironment (TME). INK-ATTAC mice bearing single cell clone YUMM tumors are treated with a combination of immune checkpoint inhibitors (aPD-1+aCTLA-4) to generate both responder and non-responder phenotypes. Upon clearance of senescent cells from the TME via injection of AP20187, the proportions of these response phenotypes shift in both pro- and anti-tumor directions. Immunohistochemical analyses show a significant negative correlation of immune infiltration with tumor size, where T cells show a 2-fold increase as tumor size is reduced as a result of ICI and AP+ICI treatment. More in-depth analysis of tumor infiltrating lymphocytes and myeloid cells through Cytometry Time of Flight (CyTOF) of a specific single cell clone reveal that the proportions of immunosuppressive myeloid cells to cytotoxic T cells are key drivers of response phenotypes in AP+ICI treated tumors. Our findings suggest that stromal cellular senescence potentially have pro- and anti-tumor effects, thus influencing both treatment efficacy and resistance mechanisms that prevent response to immune checkpoint inhibition. Citation Format: Giselle Burton Sojo, Marcel O Schmidt. Stromal senescence and response to immune checkpoint inhibition in melanoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B047.