Journal Article

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

Schmidt, Julien, Nebot-Bral, Laetitia, Chaput, Nathalie, Naigeon, Marie, Simeone, Ester, Paci, Angelo, Woerther, Paul-Louis, Mallardo, Domenico, Asvatourian, Vahe, Mateus, Christine, Ascierto, Paolo Antonio, Lacroix, Ludovic, Saulnier, Patrick, Coutzac, Clélia, Robert, Caroline, Boselli, Lisa, Carbonnel, Franck, Vozy, Aurore, Lepage, Patricia, Desbois, Mélanie, Cassard, Lydie, Soularue, Emilie, Seck, Atmane, Jouniaux, Jean-Mehdi, Grivel, Jonathan

2020

Overview

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. The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 38/77 / 631/250 / 631/67 / 64/60 / 692/4028/67/1857 / 692/53 / 82/1 / 82/16 / 82/58 / Accumulation / Animals / Anticancer properties / Antitumor activity / B7-1 Antigen - metabolism / B7-2 Antigen - metabolism / Biomarkers, Tumor - blood / Biomarkers, Tumor - metabolism / Blood / Butyrates - blood / Cancer / CD4 antigen / CD80 antigen / CD86 antigen / Colon / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - metabolism / CTLA-4 protein / Dendritic cells / Dendritic Cells - metabolism / Dietary fiber / Fatty acids / Fatty Acids, Volatile - blood / Fermentation / Gastrointestinal Microbiome - drug effects / Gastrointestinal Microbiome - genetics / Humanities and Social Sciences / Humans / Immune checkpoint / Immunological memory / Immunological tolerance / Immunotherapy / Interleukin 2 / Intestinal microflora / Ipilimumab - pharmacology / Life Sciences / Lymphocytes / Lymphocytes T / Melanoma / Memory cells / Metabolites / Metastases / Mice / Mice, Inbred BALB C / Microbiota / Microorganisms / Monoclonal antibodies / multidisciplinary / Neoplasms - blood / Neoplasms - metabolism / Propionates - blood / Propionic acid / RNA, Ribosomal, 16S - metabolism / Science / Science (multidisciplinary) / T-Lymphocytes - drug effects / T-Lymphocytes - metabolism / T-Lymphocytes, Regulatory - metabolism