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Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes

Author

Listed:
  • Jingjing Zhu

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain
    Walloon Excellence in Life Sciences and Biotechnology)

  • Céline G. Powis de Tenbossche

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain)

  • Stefania Cané

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain
    Walloon Excellence in Life Sciences and Biotechnology)

  • Didier Colau

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain)

  • Nicolas van Baren

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain)

  • Christophe Lurquin

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain)

  • Anne-Marie Schmitt-Verhulst

    (Aix Marseille Université, Inserm, CNRS)

  • Peter Liljeström

    (Karolinska Institutet)

  • Catherine Uyttenhove

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain)

  • Benoit J. Van den Eynde

    (Ludwig Institute for Cancer Research
    Université Catholique de Louvain
    Walloon Excellence in Life Sciences and Biotechnology)

Abstract

Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8+ T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy. Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas-ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors. Therefore, tumor-infiltrating lymphocytes apoptosis is a relevant mechanism of immunotherapy resistance, which could be blocked by interfering with the Fas/Fas-ligand pathway.

Suggested Citation

  • Jingjing Zhu & Céline G. Powis de Tenbossche & Stefania Cané & Didier Colau & Nicolas van Baren & Christophe Lurquin & Anne-Marie Schmitt-Verhulst & Peter Liljeström & Catherine Uyttenhove & Benoit J., 2017. "Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00784-1
    DOI: 10.1038/s41467-017-00784-1
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    Cited by:

    1. Tereza Dvorakova & Veronica Finisguerra & Matteo Formenti & Axelle Loriot & Loubna Boudhan & Jingjing Zhu & Benoit J. Van den Eynde, 2024. "Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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