Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice PMID: 39039076

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2024 Jul 22;15(1):6162. doi: 10.1038/s41467-024-50441-7.

Benjamin Assouline ^# ¹ , Rachel Kahn ^# ¹ , Lutfi Hodali ^# ¹ , Reba Condiotti ¹ , Yarden Engel ² , Ela Elyada ³ , Tzlil Mordechai-Heyn ¹ ⁴ , Jason R Pitarresi ⁵ ⁶ , Dikla Atias ⁷ , Eliana Steinberg ⁸ , Tirza Bidany-Mizrahi ² , Esther Forkosh ⁹ , Lior H Katz ⁹ , Ofra Benny ⁸ , Talia Golan ⁷ , Matan Hofree ² ¹⁰ , Sheila A Stewart ¹¹ , Karine A Atlan ¹² , Gideon Zamir ⁴ , Ben Z Stanger ¹³ , Michael Berger ² , Ittai Ben-Porath ¹⁴

Affiliations

1. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
2. The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
3. Department of Biochemistry, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
4. Department of Surgery, Hadassah Medical Center, and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
5. Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
6. Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
7. Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
8. Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
9. Department of Gastroenterology, Hadassah Medical Center, and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
10. The Rachel and Selim Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
11. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
12. Department of Pathology, Hadassah Medical Center, and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
13. Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
14. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. [email protected].
# Contributed equally.

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.