The efficacy of ipilimumab, an anti-CTLA-4 agent may be compromised by the composition of gut microbiota of patients with advanced cancer, according to findings presented at the ESMO Congress 2019 in Barcelona, Spain. In particular, short-chain fatty acids (SCFAs), which are the main metabolites of the gut microbiota and are produced in the colon through bacterial fermentation of dietary fiber, have a direct effect on immune cells.
Clelia C. Coutzac, Gustave Roussy Institute, Villejuif, France, and colleagues investigated the immunological mechanism behind the influence on immune responses provided by gut microbial metabolites in patients with melanoma and mice with cancer.
This prospective study enrolled 50 patients with metastatic melanoma who were treated with ipilimumab, which targets CTLA-4 to activate the immune system. The composition of the patients’ faecal microbiota composition was assessed by using 16S metagenomic analysis and quantitative PCR analyses to detect Faecalibacterium prausnitzii (F. prausnitzii) at baseline. In addition, concentrations of acetate, propionate, and butyrate in stool and serum samples were also evaluated in two independent patient cohorts, as well as, peripheral blood lymphocyte immunophenotypes, which were studied in parallel. Mouse models were also used to evaluate the anti-CTLA-4 anti-tumour effect with and without butyrate supplementation.
Short chain fatty acids produced by gut microbes influences the number and type of immune cells
The investigators found that high levels of SCFAs in the blood, comprised mainly of propionate or butyrate, were associated with resistance to CTLA-4 blockade following ipilimumab therapy and also associated with increased concentrations of T-regulatory cells.
Systemic butyrate levels were also linked to the enrichment of F. prausnitzii in the stool of patients. Butyrate associated with restricted accumulation of memory T cells and IL-2 impregnation following ipilimumab treatment in the patients.
These findings were supported by studies done in mice with cancer receiving anti-CTLA-4 treatment, where butyrate limited the up-regulation of CD80/CD86 expression on dendritic cells, the induction of tumour-specific T cells and the accumulation of memory T cells.
The investigators concluded that the findings from patients with melanoma receiving ipilimumab in this study were consistent with data from mice treated with anti-CTLA-4 for cancer. Taken together, these results suggest that gut microbial metabolites, including SCFAs, may favour a profile of immune tolerance that limits the activity of anti-CTLA-4 agents.
Funding was disclosed from the Gustave Roussy Cancer Campus, Fondation Gustave Roussy, the Institut national de la santé et de la recherche médicale (INSERM), the Centre national de la recherche scientifique (CNRS), SIRIC SOCRATE (INCa DGOS INSERM 6043), SIRIC SOCRATE 2.0 (INCa-DGOS-INSERM_12551), MMO programme: ANR-10IBHU-0001), the Direction General de l’Offre de Soins (DGOS; TRANSLA 12-174), and the Institut National du Cancer (INCa; 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01).
3O – Coutzac C, Jouniaux J-M, Paci A, et al. Systemic gut microbial metabolites limit the anti-tumor effect of CTLA-4 blockade in hosts with cancer.