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

Benjamin Assouline, Rachel Kahn, Lutfi Hodali, Reba Condiotti, Yarden Engel, Ela Elyada, Tzlil Mordechai-Heyn, Jason R. Pitarresi, Dikla Atias, Eliana Steinberg, Tirza Bidany-Mizrahi, Esther Forkosh, Lior H. Katz, Ofra Benny, Talia Golan, Matan Hofree, Sheila A. Stewart, Karine A. Atlan, Gideon Zamir, Ben Z. Stanger, Michael Berger and Ittai Ben-Porath ()
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Benjamin Assouline: The Hebrew University of Jerusalem
Rachel Kahn: The Hebrew University of Jerusalem
Lutfi Hodali: The Hebrew University of Jerusalem
Reba Condiotti: The Hebrew University of Jerusalem
Yarden Engel: Faculty of Medicine, The Hebrew University of Jerusalem
Ela Elyada: The Hebrew University of Jerusalem
Tzlil Mordechai-Heyn: The Hebrew University of Jerusalem
Jason R. Pitarresi: University of Massachusetts Chan Medical School
Dikla Atias: Tel Aviv University
Eliana Steinberg: Hebrew University of Jerusalem
Tirza Bidany-Mizrahi: Faculty of Medicine, The Hebrew University of Jerusalem
Esther Forkosh: Hebrew University of Jerusalem
Lior H. Katz: Hebrew University of Jerusalem
Ofra Benny: Hebrew University of Jerusalem
Talia Golan: Tel Aviv University
Matan Hofree: Faculty of Medicine, The Hebrew University of Jerusalem
Sheila A. Stewart: Washington University School of Medicine
Karine A. Atlan: Hebrew University of Jerusalem
Gideon Zamir: Hebrew University of Jerusalem
Ben Z. Stanger: University of Pennsylvania
Michael Berger: Faculty of Medicine, The Hebrew University of Jerusalem
Ittai Ben-Porath: The Hebrew University of Jerusalem

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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+ 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.

Date: 2024
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DOI: 10.1038/s41467-024-50441-7

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