Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
Clélia Coutzac, Jean-Mehdi Jouniaux, Angélo Paci, Julien Schmidt, Domenico Mallardo, Atmane Seck, Vahé Asvatourian, Lydie Cassard, Patrick Saulnier, Ludovic Lacroix, Paul‐Louis Woerther, Aurore Vozy, Marie Naigeon, Laëtitia Nebot-Bral, Mélanie Desbois, Ester Simeone, Christine Mateus, Lisa Boselli, Jonathan Grivel, Émilie Soularue, Patricia Lepage, Franck Carbonnel, Paolo A. Ascierto, Caroline Robert, Nathalie Chaput
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.