| First Author | Assouline B | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 6162 |
| PubMed ID | 39039076 | Mgi Jnum | J:360604 |
| Mgi Id | MGI:7704639 | Doi | DOI: 10.1038/s41467-024-50441-7 |
| Citation | Assouline B, et al. (2024) Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8(+) T cell activation and limit responsiveness to immunotherapy in mice. Nat Commun 15(1):6162 |
| abstractText | Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8(+) T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8(+) T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy. |
