Critical role of gut microbiota in the regulation of immune responses against glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is a most common brain tumor, and both conventional therapies and current immunotherapy are not effective at treating this tumor. Thus, unlike other cancers, a novel approach is required for glioblastoma. Commensal microbiota reside in the body and are involved in both healthy and disease states of the host. To date, research into the role of the microbiota has mainly been focused around the gastrointestinal tract. In a tissue that is as distant from the gastrointestinal tract as the brain, it is still unclear how intestinal microbes play a role in GBM. Here, we observed a distinct change in gut microbial composition and metabolisms during GBM progression using 16S rRNA sequencing in two different GBM animal models. The amount of tryptophan was significantly reduced in GBM-bearing mice, compared to that of healthy mice. Based on these results, we implemented a diet that restored tryptophan. This diet improved the survival in a commensal microbiota-dependent manner. Thus, we analyzed the gut microbiota affected by tryptophan supplementation. Surprisingly, some microbiota were restored by tryptophan treatment, comparable to that of the normal mouse. We assumed that some homeostatic microbiota may be critical for the defense against GBM. We observed improved survival in co-housed group with normal mouse and found a species that was highly different between the two groups. The colonization of this bacteria led to an increase in the survival against GBM. This bacteria required tryptophan for its growth. Cytotoxic T cells showed more potent immune response in the tumor microenvironment in tryptophan-treated mice along with the bacteria colonized mice. In addition, bacterial metabolites increased apoptotic cell death of glioma tumor cells. Collectively, we discovered the bacteria critical for GBM and found that this bacterial species potentiates CTL effector function and induces the apoptosis of tumor cells.