Blockade

Biology

CD86

Immune checkpoint

T cell

Receptor

Cancer research

Biochemistry

Immunology

Short-chain fatty acid

CD80

Ipilimumab

Immune system

CTLA-4

In vitro

Butyrate

Cytotoxic T cell

CD40

Gut flora

Chemistry

Immunotherapy

Fermentation

Nature Communications

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.

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