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Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma impair CD8+ T cell activation and limit responsiveness to immunotherapy in mice

ABSTRACT: Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions, yet the potential for targeting such senescent cells for improved therapy remains largely unknown. Here, we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs represented different previously-defined CAF subtypes. Senescent CAFs isolated from mouse and humans expressed elevated levels of immunoregulatory 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Tamar Ziv

LAB HEAD: Ittai Ben-Porath

PROVIDER: PXD053144 | Pride | 2024-06-24

REPOSITORIES: Pride

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			Action	DRS
	84250txt.rar	Other
	Seq84250_B_88min_480Ex1.raw	Raw
	Seq84251_B_88min_480Ex1.raw	Raw
	Seq84252_B_88min_480Ex1.raw	Raw
	Seq84253_B_88min_480Ex1.raw	Raw

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