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

Author

Listed:
  • Benjamin Assouline

    (The Hebrew University of Jerusalem)

  • Rachel Kahn

    (The Hebrew University of Jerusalem)

  • Lutfi Hodali

    (The Hebrew University of Jerusalem)

  • Reba Condiotti

    (The Hebrew University of Jerusalem)

  • Yarden Engel

    (Faculty of Medicine, The Hebrew University of Jerusalem)

  • Ela Elyada

    (The Hebrew University of Jerusalem)

  • Tzlil Mordechai-Heyn

    (The Hebrew University of Jerusalem
    Hebrew University of Jerusalem)

  • Jason R. Pitarresi

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Dikla Atias

    (Tel Aviv University)

  • Eliana Steinberg

    (Hebrew University of Jerusalem)

  • Tirza Bidany-Mizrahi

    (Faculty of Medicine, The Hebrew University of Jerusalem)

  • Esther Forkosh

    (Hebrew University of Jerusalem)

  • Lior H. Katz

    (Hebrew University of Jerusalem)

  • Ofra Benny

    (Hebrew University of Jerusalem)

  • Talia Golan

    (Tel Aviv University)

  • Matan Hofree

    (Faculty of Medicine, The Hebrew University of Jerusalem
    The Hebrew University of Jerusalem)

  • Sheila A. Stewart

    (Washington University School of Medicine)

  • Karine A. Atlan

    (Hebrew University of Jerusalem)

  • Gideon Zamir

    (Hebrew University of Jerusalem)

  • Ben Z. Stanger

    (University of Pennsylvania)

  • Michael Berger

    (Faculty of Medicine, The Hebrew University of Jerusalem)

  • Ittai Ben-Porath

    (The Hebrew University of Jerusalem)

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.

Suggested Citation

  • 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 & Esthe, 2024. "Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50441-7
    DOI: 10.1038/s41467-024-50441-7
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    References listed on IDEAS

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