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

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

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. ittaibp@mail.huji.ac.il.
  • # Contributed equally.
PMID: 39039076 DOI: 10.1038/s41467-024-50441-7
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.

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