Gut microbiota composition might influence the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remained unclear. Molecular mechanism whereby the gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. The main metabolites of the gut microbiota are short-chain fatty acids (SCFAs), which are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluated in mice and in patients treated with anti-CTLA-4 if SCFAs levels could be related to the clinical outcome.
Thirty-nine patients with metastatic melanoma were treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S metagenomic analysis and quantitative PCR (Q-PCR) analyses for Faecalibacterium prausnitzii (F. prausnitzii) at baseline. Stool and serum concentrations of acetate, propionate and butyrate were also evaluated in two independent cohorts in accordance with clinical outcomes. Peripheral blood lymphocytes immunophenotypes were studied in parallel. The anti-CTLA-4 anti-tumor effect was also evaluated in mice models in with or without butyrate supplementation.
Systemic butyrate was linked to Faecalibacterium prausnitzii enrichment in the stool of patients. High blood SCFAs levels (mainly propionate or butyrate) were associated with resistance to CTLA-4 blockade and were associated with a rise of Treg cells. During the course of anti-CTLA-4 treatment, butyrate limited the up-regulation of CD80/CD86 expression on dendritic cells, the induction of tumor-specific T cells and the accumulation of memory T cells in mice with cancer. In patients, restricted accumulation of memory T cells and IL-2 impregnation after ipilimumab treatment was observed.
Altogether, these results suggested that gut microbial metabolites might favor an immune tolerance profile that limits anti-CTLA-4 activity.
Institut Gustave Roussy.
This study was funded by 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 program: ANR-10IBHU-0001); Direction General de l’Offre de Soins (DGOS; TRANSLA 12-174); Institut National du Cancer (INCa; 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01). Dr. Clélia Coutzac was supported by fellowships from Fondation pour la Recherche Medicale (FRM) from 2015 to 2016.
C. Coutzac: Honoraria (self): AMGEN; Honoraria (self): Servier. L. Lacroix: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Illumina; Advisory/Consultancy: Qiagen; Advisory/Consultancy: Novartis Thermofisher; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Dyn; Speaker Bureau/Expert testimony: Vela diagnostics; Speaker Bureau/Expert testimony: Luye Pharma. F. Carbonnel: Advisory/Consultancy: enterome; Advisory/Consultancy: Amgen; Advisory/Consultancy: Astra; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Janssen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Mayoly Spindler; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pileje; Advisory/Consultancy: Roche. P.A. Ascierto: Advisory/Consultancy: Bristol Myers-Squibb; Advisory/Consultancy, Research grant/Funding (self): Roche-Genentech; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (self): Array; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: Medimmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: SunPharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera. C. Robert: Advisory/Consultancy: Roche; Advisory/Consultancy: GSK; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS. N. Chaput: Research grant/Funding (self): Cytune Pharma; Research grant/Funding (self): GSK; Speaker Bureau/Expert testimony, Research grant/Funding (self): Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.