Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma suppress CD8+ T cell activation and inhibit response to immune checkpoint therapy [Cultured_Human_Mouse]

Senescent cells appear within tumors and their stroma, exerting complex pro- and anti-tumorigenic functions. The effects of senescent tumor stromal cells are mostly unknown, as is the potential for targeting such senescent cells for improved therapy. Here we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic adenocarcinomas and in premalignant pancreatic lesions. Senescent CAFs show reduced proliferation, and are often associated with the inflammatory CAF (iCAF) subtype. We isolated and characterized senescent CAFs from mouse models and directly from human patients, and found that they express elevated levels of immune-regulatory genes. In a panel of mouse PDACs, high levels of senescent CAFs correlated with low T cell infiltration. Removal of senescent CAFs from PDAC stroma, either genetically or through treatment with the senolytic drug ABT-199 (venetoclax), a Bcl2 inhibitor, increased rates of activated cytotoxic CD8+ T cells within tumors. Conversely, activation of CAF senescence within PDACs led to reduced CD8+ T cell numbers. Media from senescent PDAC CAFs inhibited T cell proliferation and activation. We show that implanted PDAC tumors show improved response to immune checkpoint therapy when co-treated with the senolytic drug. These results reveal that the presence of senescent CAFs in PDAC stroma acts to repress cytotoxic T cell activity, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.