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

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 previo...

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Published in:	Nature communications Vol. 15; no. 1; pp. 6162 - 16
Main Authors:	Assouline, Benjamin, Kahn, Rachel, Hodali, Lutfi, Condiotti, Reba, Engel, Yarden, Elyada, Ela, Mordechai-Heyn, Tzlil, Pitarresi, Jason R., Atias, Dikla, Steinberg, Eliana, Bidany-Mizrahi, Tirza, Forkosh, Esther, Katz, Lior H., Benny, Ofra, Golan, Talia, Hofree, Matan, Stewart, Sheila A., Atlan, Karine A., Zamir, Gideon, Stanger, Ben Z., Berger, Michael, Ben-Porath, Ittai
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 22-07-2024 Nature Publishing Group Nature Portfolio
Subjects:	13 13/106 13/51 38/1 38/39 38/77 38/91 631/80/509 64 64/110 64/60 692/4028/67/1504/1713 692/4028/67/327 Adenocarcinoma Adenocarcinoma - genetics Adenocarcinoma - immunology Adenocarcinoma - pathology Adenocarcinoma - therapy Animal models Animals Bcl-2 protein Bridged Bicyclo Compounds, Heterocyclic Cancer Cancer therapies Cancer-Associated Fibroblasts - immunology Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - immunology Carcinoma, Pancreatic Ductal - pathology Carcinoma, Pancreatic Ductal - therapy CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell activation Cell culture Cell Line, Tumor Cellular Senescence - immunology Cytotoxicity Female Fibroblasts Humanities and Social Sciences Humans Immune checkpoint Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunotherapy Immunotherapy - methods Lymphocyte Activation - immunology Lymphocytes Lymphocytes T Male Mice Mice, Inbred C57BL multidisciplinary Pancreas Pancreatic cancer Pancreatic carcinoma Pancreatic Neoplasms - genetics Pancreatic Neoplasms - immunology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - therapy Science Science (multidisciplinary) Senescence Stroma Sulfonamides - pharmacology Sulfonamides - therapeutic use Tumors
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Summary:	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. Cancer-associated fibroblasts (CAFs) are abundant in the stroma of pancreatic ductal carcinoma (PDAC) tumors. In this study, the authors demonstrate using human samples and mouse models that senescent CAFs impair CD8 + T cell responses and may contribute to poor responsiveness to immunotherapy in PDAC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-50441-7