Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression

Abstract

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.

Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models

“…Several studies using syngeneic tumor models in immune-competent mice showed that the SASP can prevent tumor rejection by inducing an immunosuppressive TME 7–10 . For example, prolonged exposure to SASP factors such as type 1 interferon and IL-6 were shown to downregulate immune cell functions 11–13 and to interfere with the tumor immune response mediated by T and NK cells 7–9 .…”