Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8 + T cell activation and limit responsiveness to immunotherapy in mice.
Benjamin AssoulineRachel KahnLutfi HodaliReba CondiottiYarden EngelEla ElyadaTzlil Mordechai-HeynJason R PitarresiDikla AtiasEliana SteinbergTirza Bidany-MizrahiEsther ForkoshLior H KatzOfra BennyTalia GolanMatan HofreeSheila A StewartKarine A AtlanGideon ZamirBen Z StangerMichael BergerIttai Ben-PorathPublished in: Nature communications (2024)
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.
Keyphrases
- cancer therapy
- induced apoptosis
- cell cycle arrest
- drug delivery
- genome wide
- high fat diet induced
- stem cells
- cell death
- high grade
- dna damage
- endoplasmic reticulum stress
- risk factors
- climate change
- adipose tissue
- metabolic syndrome
- insulin resistance
- anti inflammatory
- human health
- combination therapy
- wild type
- pi k akt
- dna methylation
- genome wide identification