| Autor: |
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, Ittai Ben-Porath |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-16 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-50441-7 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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