Abstract 6870: Immunological aging in triple negative breast cancer leads to a chronic interferon phenotype and immune cell exhaustion that impedes response to therapy

Abstract Age is the biggest risk factor for developing most forms of cancer, and understanding how age impacts cancer progression is critical to improving responses to therapy. As we age immune function declines suggesting that therapeutic responses, particularly to immunotherapies, will also change with age. Early clinical trial data suggests that there are age-associated responses to immunotherapies. Clinical trials, however, are not designed to reflect patient chronological and immunological ages - over 50% of breast cancer patients are over the age of 60, yet less than 25% of patients in clinical trials are in this age range. Here, we utilize a preclinical mouse model of immunological aging to understand how aging impacts immune responses to triple-negative breast cancer (TNBC). Immunologically young (8 weeks old) and aged (~12 months old) FVB mice were orthotopically injected with syngeneic Met1 TNBC cells. We previously established that this preclinical model mimics human immunological aging and enables us to better understand how age impacts disease progression and therapeutic responses. Once tumors became palpable, mice were treated with paclitaxel or vehicle control and/or anti-PDL1 to mimic first-line therapeutic strategies. Tumors grew significantly faster in young control mice compared to aged, but young mice had a more robust response to therapy. Notably, only young mice had a significant benefit of combo therapy (paclitaxel + anti-PDL1) over monotherapy alone. Tumors in aged mice had significantly more infiltration of CD8+ cytotoxic T cells and FOXP3+ inhibitory T-regulatory cells compared to young control mice, yet only tumors in young mice exhibited an increase in T cell infiltration with chemo or immunotherapy. Depletion of either CD8+ or CD4+ T cells in immune-competent FVB mice both led to a complete loss of age-associated differences in tumor growth. RNA sequencing analysis indicated that the infiltrating T cells in aged mice may be exhausted due to a chronic interferon phenotype, as indicated by enrichments of interferon alpha, interferon gamma, and IL2 signaling pathways, as well as expression of RIPK1, TNFa, and the immune exhaustion markers PD1, CTLA4, TIM3, and LAG3. Analysis of published single cell RNAseq data indicated the same interferon response pathways enriched with age in human TNBC, particularly in the T cell compartment. Our findings show that the aging immune microenvironment significantly impacts tumor progression and that a chronic interferon phenotype with age may lead to T cell exhaustion and impaired therapeutic responses. This work suggests that targeting interferon signaling may lead to improved therapeutic responses. Together these findings demonstrate how immunological aging can impact disease progression and response to therapy and highlight the importance of developing age-stratified treatment strategies. Citation Format: Milos Spasic, Adrienne Parsons, Gregory Goreczny, Qiuchen Guo, Abigail Recko, Elizabeth Mittendorf, Peter van Galen, Sandra McAllister. Immunological aging in triple negative breast cancer leads to a chronic interferon phenotype and immune cell exhaustion that impedes response to therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6870.