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 upregulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumorspecific 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 Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients

“…However, limitations in the reconstitution of transplanted fecal microbiota in mice should be considered as one of the factors of such discrepancies [ 128 ]. Moreover, similar results were obtained Coutzac et al [ 129 ] in studies on 38 fecal samples collected from metastatic melanoma. Gut microbiota enriched with Faecalibacterium spp.…”

“…However, there is a limited number of communications presenting this correlation. Coutzac et al [ 129 ] demonstrated that anti-CTLA-4 therapy efficacy is inhibited by systemic SCFAs. They measured serum concentrations of three SCFAs, i.e., acetate, propionate, and butyrate in metastatic melanoma patients treated with ipilimumab ( n = 85) and observed a negative correlation between serum levels of butyrate and propionate and clinical outcomes.…”

Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

“…Moreover, patients from cluster A exhibited lower circulating CD4 + Tregs. 41,44 An additional study including 39 patients focusing on various ICI regimens (anti-CTLA-4, anti-PD-1, or the combination of both) corroborated the finding that the metagenomics-based analysis of the gut microbiota composition can predict clinical outcome of immune checkpoint blockade in MM patients. It also showed with the bias of a limited number of patients in each immunotherapy arm that the best species predictive for response are different in each regimen.…”

“…40 In fact, high levels of butyrate and propionate in the blood are associated with resistance to CTLA-4 blockade and an increase in the abundance of Treg cells. 41 However, these results are in contrast with a small Japanese study (52 patients suffering from a broad range of cancer types) showing that high concentrations of fecal and plasma SCFAs were associated with a response to PD-1 treatment and longer progression-free survival (PFS). 42 Additional research is needed to clarify the association between fecal and plasma SCFAs and the efficacy of ICIs.…”

Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells

“…Recent studies indicate that the composition of the microbiome is one of the factors associated with clinical outcome in patients undergoing treatment with immune checkpoint blockade [ 71 , 72 ]. Work done on French cohorts treated with ipilimumab, a blocking CTL-4 therapeutic, revealed that low baseline expression of butyrate and propionate was associated with longer progression-free survival [ 73 ]. Indeed, butyrate reduced the efficacy of CTLA-4 blockade in a mouse model, and the mechanism by which SCFAs restrained ipilimumab effectiveness involved the modulation of B7 (CD80 and CD86) expression on the surface of DCs and inducible T-cell costimulator (ICOS) within T cells.…”