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

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.

SUBMITTER: Coutzac C

PROVIDER: S-EPMC7195489 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Coutzac Clélia C Jouniaux Jean-Mehdi JM Paci Angelo A Schmidt Julien J Mallardo Domenico D Seck Atmane A Asvatourian Vahe V Cassard Lydie L Saulnier Patrick P Lacroix Ludovic L Woerther Paul-Louis PL Vozy Aurore A Naigeon Marie M Nebot-Bral Laetitia L Desbois Mélanie M Simeone Ester E Mateus Christine C Boselli Lisa L Grivel Jonathan J Soularue Emilie E Lepage Patricia P Carbonnel Franck F Ascierto Paolo Antonio PA Robert Caroline C Chaput Nathalie N

Nature communications 20200501 1

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 ...[more]

PMID: 32358520

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Project description:IntroductionColorectal cancer (CRC) is a leading cause of death worldwide and its growth can either be promoted or inhibited by the metabolic activities of intestinal microbiota. Short chain fatty acids (SCFAs) are microbial metabolites with potent immunoregulatory properties yet there is a poor understanding of how they directly regulate immune modulating pathways within the CRC cells.MethodsWe used engineered CRC cell lines, primary organoid cultures, orthotopic in vivo models, and patient CRC samples to investigate how SCFA treatment of CRC cells regulates their ability to activate CD8+ T cells.ResultsCRC cells treated with SCFAs induced much greater activation of CD8+ T cells than untreated CRC cells. CRCs exhibiting microsatellite instability (MSI) due to inactivation of DNA mismatch repair were much more sensitive to SCFAs and induced much greater CD8+ T cell activation than chromosomally instable (CIN) CRCs with intact DNA repair, indicating a subtype-dependent response to SCFAs. This was due to SCFA-induced DNA damage that triggered upregulation of chemokine, MHCI, and antigen processing or presenting genes. This response was further potentiated by a positive feedback loop between the stimulated CRC cells and activated CD8+ T cells in the tumor microenvironment. The initiating mechanism in the CRCs was inhibition of histone deacetylation by the SCFAs that triggered genetic instability and led to an overall upregulation of genes associated with SCFA signaling and chromatin regulation. Similar gene expression patterns were found in human MSI CRC samples and in orthotopically grown MSI CRCs independent of the amount of SCFA producing bacteria in the intestine.DiscussionMSI CRCs are widely known to be more immunogenic than CIN CRCs and have a much better prognosis. Our findings indicate that a greater sensitivity to microbially produced SCFAs contributes to the successful activation of CD8+ T cells by MSI CRCs, thereby identifying a mechanism that could be therapeutically targeted to improve antitumor immunity in CIN CRCs.

Dataset Information

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

Publications

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

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