TY - JOUR
T1 - Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
AU - Coutzac, Clélia
AU - Jouniaux, Jean Mehdi
AU - Paci, Angelo
AU - Schmidt, Julien
AU - Mallardo, Domenico
AU - Seck, Atmane
AU - Asvatourian, Vahe
AU - Cassard, Lydie
AU - Saulnier, Patrick
AU - Lacroix, Ludovic
AU - Woerther, Paul Louis
AU - Vozy, Aurore
AU - Naigeon, Marie
AU - Nebot-Bral, Laetitia
AU - Desbois, Mélanie
AU - Simeone, Ester
AU - Mateus, Christine
AU - Boselli, Lisa
AU - Grivel, Jonathan
AU - Soularue, Emilie
AU - Lepage, Patricia
AU - Carbonnel, Franck
AU - Ascierto, Paolo Antonio
AU - Robert, Caroline
AU - Chaput, Nathalie
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084153708&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16079-x
DO - 10.1038/s41467-020-16079-x
M3 - Article
C2 - 32358520
AN - SCOPUS:85084153708
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2168
ER -