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Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

Author

Listed:
  • Clélia Coutzac

    (Laboratoire d’Immunomonitoring en Oncologie
    Université Paris-Saclay, Faculté de Médicine
    Faculté de Médicine
    Assistance Publique-Hôpitaux de Paris)

  • Jean-Mehdi Jouniaux

    (Laboratoire d’Immunomonitoring en Oncologie
    Université Paris-Saclay, Faculté de Médicine)

  • Angelo Paci

    (Vectorologie et thérapeutiques anticancéreuses
    Pharmacology and Drug Analysis Department
    Faculté de Pharmacie)

  • Julien Schmidt

    (Laboratoire d’Immunomonitoring en Oncologie
    Université Paris-Saclay, Faculté de Médicine)

  • Domenico Mallardo

    (Instituto Nazionale Tumori- IRCCS –Fondazione G. Pascale)

  • Atmane Seck

    (Vectorologie et thérapeutiques anticancéreuses
    Pharmacology and Drug Analysis Department)

  • Vahe Asvatourian

    (Biostatistics and Epidemiology Unit
    UVSQ, Inserm, CESP)

  • Lydie Cassard

    (Laboratoire d’Immunomonitoring en Oncologie)

  • Patrick Saulnier

    (Genomic platform Molecular Biopathology unit and Biological Resource Center)

  • Ludovic Lacroix

    (Genomic platform Molecular Biopathology unit and Biological Resource Center)

  • Paul-Louis Woerther

    (Microbiology unit)

  • Aurore Vozy

    (Laboratoire d’Immunomonitoring en Oncologie)

  • Marie Naigeon

    (Laboratoire d’Immunomonitoring en Oncologie)

  • Laetitia Nebot-Bral

    (Université Paris-Saclay, Faculté de Médicine
    Stabilité génétique et oncogenèse)

  • Mélanie Desbois

    (Laboratoire d’Immunomonitoring en Oncologie)

  • Ester Simeone

    (Instituto Nazionale Tumori- IRCCS –Fondazione G. Pascale)

  • Christine Mateus

    (Department of Medicine)

  • Lisa Boselli

    (Laboratoire d’Immunomonitoring en Oncologie)

  • Jonathan Grivel

    (Laboratoire d’Immunomonitoring en Oncologie)

  • Emilie Soularue

    (Laboratoire d’Immunomonitoring en Oncologie
    Université Paris-Saclay, Faculté de Médicine
    Assistance Publique-Hôpitaux de Paris)

  • Patricia Lepage

    (Micalis Institute)

  • Franck Carbonnel

    (Université Paris-Saclay, Faculté de Médicine
    Assistance Publique-Hôpitaux de Paris)

  • Paolo Antonio Ascierto

    (Instituto Nazionale Tumori- IRCCS –Fondazione G. Pascale)

  • Caroline Robert

    (Université Paris-Saclay, Faculté de Médicine
    Department of Medicine)

  • Nathalie Chaput

    (Laboratoire d’Immunomonitoring en Oncologie
    Faculté de Pharmacie
    Stabilité génétique et oncogenèse)

Abstract

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.

Suggested Citation

  • Clélia Coutzac & Jean-Mehdi Jouniaux & Angelo Paci & Julien Schmidt & Domenico Mallardo & Atmane Seck & Vahe Asvatourian & Lydie Cassard & Patrick Saulnier & Ludovic Lacroix & Paul-Louis Woerther & Au, 2020. "Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16079-x
    DOI: 10.1038/s41467-020-16079-x
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    Cited by:

    1. Gabriel Lachance & Karine Robitaille & Jalal Laaraj & Nikunj Gevariya & Thibault V. Varin & Andrei Feldiorean & Fanny Gaignier & Isabelle Bourdeau Julien & Hui Wen Xu & Tarek Hallal & Jean-François Pe, 2024. "The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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