Senescent cancer-associated fibroblasts modulate the immune composition of the tumor microenvironment in pancreatic cancer

Senescence is a state acquired by cells in response to stress or damage. Senescence is characterized by cell cycle arrest, changes in morphology and metabolism, and acquisition of an inflammatory secretory phenotype. Senescent cells are a subject of study with regards to their roles in organismal aging and pathologies associated with it. In cancer, their roles are complex, as they can either inhibit or promote tumorigenesis. My research focuses on the roles of senescent Cancer-Associated Fibroblasts (senCAFs), a subset of the stromal supporting cancer-associated fibroblasts (CAFs), highly active in organizing the tumor microenvironment (TME), and surrounding cancer cells. SenCAFs are present in mouse pancreatic tumors and resected human tumors. By using models that involve the addition or suppression of senCAFs in mice with pancreatic cancer, we observed their immunosuppressive effects. We found that senCAFs inhibit T cell activation and that removing them of mouse PDAC leads to increased T cell infiltration and activation. Treating pancreatic ductal adenocarcinoma (PDAC)-bearing mice with a senolytic drug improved the efficacy of immune checkpoint therapies (ICT) and reduced tumor burden. These results reveal that stromal cell senescence promotes an immune-suppressive tumor microenvironment in pancreatic cancer and suggest that targeting senescent cells may provide a tool to enhance the effects of immunotherapy for specific patient subsets.