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Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
Clélia Coutzac (Centre National de la Recherche Scientifique, Inserm), Jean-Mehdi Jouniaux (Centre National de la Recherche Scientifique, Inserm), Angélo Paci (Centre National de la Recherche Scientifique, Université Paris-Saclay), Julien Schmidt (Centre National de la Recherche Scientifique, Inserm), Domenico Mallardo (Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Fondazione IRCCS Istituto Nazionale dei Tumori), Atmane Seck (Centre National de la Recherche Scientifique, Université Paris-Saclay), Vahé Asvatourian (Inserm, Université de Versailles Saint-Quentin-en-Yvelines), Lydie Cassard (Centre National de la Recherche Scientifique, Inserm), Patrick Saulnier (Centre National de la Recherche Scientifique, Inserm), Ludovic Lacroix (Centre National de la Recherche Scientifique, Inserm), Paul‐Louis Woerther (Institut Gustave Roussy), Aurore Vozy (Centre National de la Recherche Scientifique, Inserm), Marie Naigeon (Centre National de la Recherche Scientifique, Inserm), Laëtitia Nebot-Bral (Centre National de la Recherche Scientifique, Université Paris-Saclay), Mélanie Desbois (Centre National de la Recherche Scientifique, Inserm), Ester Simeone (Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Fondazione IRCCS Istituto Nazionale dei Tumori), Christine Mateus (Institut Gustave Roussy), Lisa Boselli (Centre National de la Recherche Scientifique, Inserm), Jonathan Grivel (Centre National de la Recherche Scientifique, Inserm), Émilie Soularue (Centre National de la Recherche Scientifique, Inserm), Patricia Lepage (AgroParisTech, Université Paris-Saclay), Franck Carbonnel (Université Paris-Saclay, Assistance Publique – Hôpitaux de Paris), Paolo A. Ascierto (Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"), Caroline Robert (Université Paris-Saclay, Institut Gustave Roussy), Nathalie Chaput (Centre National de la Recherche Scientifique, Inserm)
Résumé : 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.