Senescent Cancer-associated Fibroblasts in Pancreatic Adenocarcinoma Restrict CD8 T Cell Activation and Limit Responsiveness to Immunotherapy in Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jul 22

PMID 39039076

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Revealing the role of cancer-associated fibroblast senescence in prognosis and immune landscape in pancreatic cancer.

Liu L, Huang H, Cheng B, Xie H, Peng W, Cui H iScience. 2025; 28(1):111612.

PMID: 39834857 PMC: 11742819. DOI: 10.1016/j.isci.2024.111612.

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