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

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

doi:10.1038/s41467-024-50441-7

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.

Authors

Benjamin Assouline^#¹, Rachel Kahn^#¹, Lutfi Hodali^#¹, Reba Condiotti¹, Yarden Engel², Ela Elyada³, Tzlil Mordechai-Heyn^{1

4}, Jason R Pitarresi^{5

6}, Dikla Atias⁷, Eliana Steinberg⁸, Tirza Bidany-Mizrahi², Esther Forkosh⁹, Lior H Katz⁹, Ofra Benny⁸, Talia Golan⁷, Matan Hofree^{2

10}, Sheila A Stewart¹¹, Karine A Atlan¹², Gideon Zamir⁴, Ben Z Stanger¹³, Michael Berger², Ittai Ben-Porath¹⁴

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.

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.

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / immunology
Adenocarcinoma / pathology
Adenocarcinoma / therapy
Animals
Bridged Bicyclo Compounds, Heterocyclic
CD8-Positive T-Lymphocytes* / immunology
Cancer-Associated Fibroblasts* / immunology
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / immunology
Carcinoma, Pancreatic Ductal* / pathology
Carcinoma, Pancreatic Ductal* / therapy
Cell Line, Tumor
Cellular Senescence* / immunology
Female
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immunotherapy* / methods
Lymphocyte Activation / immunology
Male
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / immunology
Pancreatic Neoplasms* / pathology
Pancreatic Neoplasms* / therapy
Sulfonamides* / pharmacology
Sulfonamides* / therapeutic use

Substances

venetoclax
Sulfonamides
Immune Checkpoint Inhibitors
Bridged Bicyclo Compounds, Heterocyclic

Abstract

MeSH terms

Substances

Grants and funding