Abstract 85: Senescent cells promote breast cancer tumorigenesis

Abstract Age is the largest risk factor for breast cancer development. While numerous changes arise with age, we posit that the accumulation of p16INKA4 (p16)+ senescent stromal cells—which express cytokines, chemokines, and enzymes together recognized as senescence-associated secretory phenotype (SASP)—promote cancer progression. Indeed, high p16 positivity in stroma strongly correlates with breast cancer recurrence. To investigate how senescent stroma impact tumorigenesis, we crossed MMTV-PyMT (PyMT) mice that spontaneously develop mammary tumors to INK-ATTAC (INK) mice, which allows selective elimination of p16+ cells. Depletion of p16+ stroma in PyMT/INK mice led to a significantly delayed tumor onset and changes in tumor-infiltrating immune cells, both of which could be recapitulated by treating PyMT mice with a senolytic drug. scRNA-seq analyses of murine and human tumor samples revealed that senescence is restricted to a specific cancer associated fibroblasts (CAF) subpopulation that expresses numerous immune and extracellular matrix SASP factors that could impact T cells and Natural Killer (NK) cells. We refer to these cells as senescent CAFs (senCAFs). To assess the impact of senCAFs on T and NK cells’ anti-tumor effect, we depleted each population and found that the elimination of senCAFs no longer restricted tumor development in the absence of NK cells. We thus focused on addressing how senCAFs modulate NK cell function. Together our data highlight how senescent CAFs contribute to mammary gland tumorigenesis by modifying tumor microenvironment. Citation Format: Jiayu (Jennifer) Ye, Ana Paula Delgado, Qihao Ren, Robert S. Powers, Sheila A. Stewart. Senescent cells promote breast cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 85.