Abstract 6056: Aging accelerates breast tumorigenesis though cancer immunosuppression

Abstract Age is a major risk factor for breast cancer. However, the mechanisms by which age affects breast cancer initiation and progression is not fully understood. Unfortunately, there is a paucity of mouse with which to study the role of aging in cancer, especially the impact of aging on the epithelial tumor cells-of-origin. To address this for breast cancer, we established a mouse model in which breast cancer was induced de novo in young and old wildtype mice through intraductal injection of a lentivirus carrying the breast cancer oncogene HER2/neu. Consistent with human data, breast tumors in the old mice grew more rapidly than in young mice. Old mice exhibited more aggressive, invasive and higher grade breast tumor lesions. GeoMx whole-transcriptome spatial transcriptomics revealed that old tumor cells upregulated genes associated with invasion, epithelial-to-mesenchymal transition, cell migration, blood vessel development, and extracellular matrix formation, while downregulating genes related to immune response, interferon gamma response, and antigen presentation. Specifically, several chemokines were downregulated in old tumor cells, with Cxcl9 and Cxcl10 (hereafter Cxcl9/10) being the most prominent, an observation confirmed by RNAscope and immunostaining. Expression of Cxcl9/10 is known to attract Cd8+ and Cd4+ T cells through binding to the T cell Cxcr3 receptor, thereby facilitating anti-tumor T cell infiltration into tumors. We observed fewer tumor infiltrating Cd4+ and Cd8+ T cells in old tumors. Simultaneous depletion of Cd4 and Cd8 T cells significantly accelerated tumor growth in young mice but not in old mice. Blocking Cxcr3 in young mice accelerated tumor growth and reduced T cell infiltration, while enhancing Cxcl9/10 expression slowed down the tumor growth in old mice. These results suggest that age-associated downregulation of Cxcl9/10 in tumor cells is responsible for an impaired anti-tumor immune response in aged tissue. Furthermore, scATACseq revealed that Cxcl9/10 gene regions were less accessible in old tumor tissues. Taken together, these results suggest that age-associated downregulation of Cxcl9/10 in tumor cells is responsible for an impaired anti-tumor immune response in aged tissue, with epigenetic rewiring playing a critical role in this process. Citation Format: Shanshan Yin, Kay Yeung, Jing Yang, Peter D. Adams. Aging accelerates breast tumorigenesis though cancer immunosuppression [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 6056.