Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression

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…

• CF
  Center for Cancer Research

  Awards: CA217208, P30CA091842, CA21720605, CA113275, CA275212, CA271721, CA254060, CA223758
• UD
  U.S. Department of Defense

  Awards: BC181712, 21702-5014
• FF
  Foundation for Barnes-Jewish Hospital

  Award: 3770 and 4642
• CD
  Children's Discovery Institute

  Awards: CDI-CORE-2019-813, CDI-CORE-2015-505
• AJ
  Alvin J. Siteman Cancer Center

  Award: P30CA091842
• NI
  National Institutes of Health

  Awards: CA113275, AG059244, CA223758, P30CA091842, R01 CA223758
• CF
  Center for Cellular Imaging, Washington University
• NI
  National Institute on Aging

  Award: AG059244
• NC
  National Cancer Institute

  Awards: R01CA247362, CA217208, CA113275, P30CA091842
• NI
  National Institute of General Medical Sciences

  Award: GM7200-49
• DO
  Division of Diabetes, Endocrinology, and Metabolic Diseases

  Award: DK122633
• UA
  U.S. Army Medical Research Acquisition Activity

  Awards: 21702-5014, MD 21702-5014