Abstract 1213: Immune aging impedes intratumoral T-cell activity to reduce response to therapy in triple negative breast cancer

Abstract Age is the biggest risk factor for developing most cancers, including breast cancer. While over 50% of cancer cases occur in patients over 65, fewer than 25% of patients enrolled in clinical trials are in this age range. Furthermore, most preclinical trials are performed in young mice, meaning that from the preclinical through clinical stages trials do appropriately reflect the patients most affected by cancer. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer which lacks targeted therapies, and as such is typically treated with a combination of chemotherapy, such as paclitaxel (PTX), and immunotherapy, such as anti-PDL1. With age, there is also a characteristic change in immune fitness - expansion of myeloid cells, increase in inflammatory cytokines, decrease in naïve T cell pools - suggesting that patients of different ages will respond differently to immunotherapies which rely on immune fitness. It is not completely known how age impacts TNBC therapeutic responses, as most studies have been underpowered to properly study the impact of age. We utilized a preclinical model where young (8-10 week old) and aged (12-16 month old) FVB mice display hallmarks of immune aging in their peripheral blood. Orthotopic injection of syngeneic TNBC tumor cells, Met1, results in tumors that are more aggressive in young mice, but also more responsive to anti-PDL1, PTX, and particularly to a combination of both. This is accompanied by an increase in CD8+ cytotoxic T-cell infiltration in aged control mouse tumors, but no further increase in infiltration with treatment. This is opposite in young mice which see a robust increase in T-cell infiltration with treatment, highlighting their improved response to therapy. Depletion of cytotoxic CD8+ T-cells leads to faster tumor growth in both young and aged mice, but completely abrogates any age-associated difference in tumor growth, demonstrating the critical role of immune aging in this age-associated phenotype. Bulk RNAseq suggests that tumors in aged mice are enriched for IFNg-response programs. Treatment with anti-IFNg antibodies alone has no impact on tumor growth, but completely blocks any response to anti-PDL1 in young mice, with no impact on the aged mouse anti-PDL1 response. Flow cytometry reveals that the tumor-infiltrating CD8s in aged mice have decreased CD107a and IFNg expression, markers of CD8+ T-cell activity and activation. Further, IFNg+ CD8s in aged mice show signs of increased T-cell exhaustion by PD1, TIM3, and LAG3 expression. These data demonstrate that immune aging significantly impacts T-cell function leading to age-associated differences in disease progression and therapeutic response. Our continued work to target T-cell activity and infiltration via IFNg-response programs in the tumor microenvironment will lead to age-stratified treatment options and improved therapeutic outcomes for patients of all ages. Citation Format: Milos Spasic, Melissa Dolan, Adrienne Parsons, Dimitry Lineker, Elizabeth Mittendorf, Peter van Galen, Sandra McAllister. Immune aging impedes intratumoral T-cell activity to reduce response to therapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1213.