Comprehensive multi-omic analysis reveals bifidobacterium strain-specific enhancement of anti-cancer immunity

Abstract

The gut microbiome of cancer patients is believed to influence the development of tumors, as well as the efficacy of anti-tumor therapies, including anti-PD-1 antibody. However, the genomic characteristics and detailed functions of anti-tumor bacterial strains have not been fully clarified. In this study, I utilized an integrated approach, involving metagenome, bacterial whole genome/transcriptome, mouse intestinal transcriptome, and mouse serum metabolome analysis, to decipher whether bacterial strain-specific differences influence the efficacy of cancer therapeutics in vivo. By analyzing the gut microbiomes of 96 Non-small cell lung cancer (NSCLC) patients and 139 healthy controls, I found that Bifidobacterium bifidum was significantly abundant in NSCLC patients responsive to cancer treatment, as compared to non-responders. Using a syngeneic mouse model, I further showed that four B. bifidum strains reduce tumor burden in vivo, but only half of the strains work synergistically with the cancer therapeutic drugs, anti-PD-1 antibody or oxaliplatin, to improve tumor clearance. These synergistic B. bifidum strains modulate expression of immune-related genes in mouse intestinal tissue and appear to act by potentiating the production of interferon-gamma (INF-γ). Bacterial genome sequencing and transcriptomic analyses, combined with metabolomic analyses of serum from syngeneic tumor mice, further suggest that these synergistic strains promote INF-γ-mediated tumor clearance via the enhanced biosynthesis of bacterial immunogenic molecules and metabolites