TY - JOUR
T1 - Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice
AU - Assouline, Benjamin
AU - Kahn, Rachel
AU - Hodali, Lutfi
AU - Condiotti, Reba
AU - Engel, Yarden
AU - Elyada, Ela
AU - Mordechai-Heyn, Tzlil
AU - Pitarresi, Jason R.
AU - Atias, Dikla
AU - Steinberg, Eliana
AU - Bidany-Mizrahi, Tirza
AU - Forkosh, Esther
AU - Katz, Lior H.
AU - Benny, Ofra
AU - Golan, Talia
AU - Hofree, Matan
AU - Stewart, Sheila A.
AU - Atlan, Karine A.
AU - Zamir, Gideon
AU - Stanger, Ben Z.
AU - Berger, Michael
AU - Ben-Porath, Ittai
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85199189258
U2 - 10.1038/s41467-024-50441-7
DO - 10.1038/s41467-024-50441-7
M3 - Article
C2 - 39039076
AN - SCOPUS:85199189258
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6162
ER -