Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8<sup>+</sup> T cell activation and limit responsiveness to immunotherapy in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39039076.
- Also identified by DOI 10.1038/s41467-024-50441-7 and PMC identifier 11263607.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sup>+</sup> 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<sup>+</sup> T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
Medical subject headings
- Cancer-Associated Fibroblasts
- Pancreatic Neoplasms
- CD8-Positive T-Lymphocytes
- Carcinoma, Pancreatic Ductal
- Cellular Senescence
- Immunotherapy
- Sulfonamides