Beneficial Effect of Antibiotics and Microbial Metabolites on Expanded Vδ2Vγ9 T Cells in Hepatocellular Carcinoma Immunotherapy

Abstract

Animal experiments and clinical trials have shown that the gut microbiota modulates host immunity and immune checkpoint-mediated responses to tumor cells. However, it remains unclear whether microbiota can also play a role in the tumor immune response of γδT cells, a kind of cell that targets cancer directly. Here, we report that microbiota dysbiosis induced by antibiotics enhanced γδT cell efficacy during tumor therapy in a mouse model. Further microbiota and metabolite analysis revealed that the alteration of γδT cell cytotoxicity might be closely associated with specific metabolites, which are produced by intestinal bacteria and stimulate γδT cells to release more cytotoxic cytokines, such as granzyme B and perforin. Among the metabolites that we analyzed, 3-indopropionic acid (IPA) showed the highest concentration in antibiotic-treated mice and can improve the cytotoxic ability of γδT cells both in vitro and in vivo . Our research determined how the gut microbiota can influence the antitumor ability of γδT cells and identified potential intermediate molecules that connect the gut microbiota and γδT cells.

The microbiome, gastrointestinal cancer, and immunotherapy

“…3‐Indolepropionic acid, a bacterial metabolite from tryptophan, was found to be substantially elevated in the cecal contents of antibiotics‐treated mice 79 . 3‐Indolepropionic acid administration, in vitro and in vivo , enhanced cytotoxicity of γδT cells against HCC cells 79 …”

“…Nonetheless, manipulating the gut microbiota could be an approach to potentiate immunotherapy against HCC. In a subcutaneous HCC xenograft tumor model, periodical antibiotic treatment (penicillin, chloramphenicol, and streptomycin) enhanced the antitumor efficacy of γδT cell immunotherapy 79 . 3‐Indolepropionic acid, a bacterial metabolite from tryptophan, was found to be substantially elevated in the cecal contents of antibiotics‐treated mice 79 .…”

“…In a subcutaneous HCC xenograft tumor model, periodical antibiotic treatment (penicillin, chloramphenicol, and streptomycin) enhanced the antitumor efficacy of γδT cell immunotherapy 79 . 3‐Indolepropionic acid, a bacterial metabolite from tryptophan, was found to be substantially elevated in the cecal contents of antibiotics‐treated mice 79 . 3‐Indolepropionic acid administration, in vitro and in vivo , enhanced cytotoxicity of γδT cells against HCC cells 79 …”

Host–Microbiota Interactions in Liver Inflammation and Cancer

“…Notably, some species, including A. muciniphila and Ruminococcaceae spp., were found to be enriched in the gut of HCC patients that respond to anti-PD-1 immune-checkpoint blockade compared to non-responders [37]. Interestingly, the microbial metabolite 3-indopropionic acid (IPA) was recently shown to enhance the tumorilytic activity of γδ T cells in a murine model of HCC [38]. However, additional studies are warranted to fully understand how the microbiota control antitumor immunity.…”

Immuno-reactive cancer organoid model to assess effects of the microbiome on cancer immunotherapy

“…The interaction between these metabolites and the host immune system is key to understanding how the microbiome can alter ICB efficacy. This also means that specific positive indicator metabolites could be used as a predictive measure of ICB response 17 . Therefore, it is highly advantageous to create a flexible, high-throughput model that can examine the roles of multiple specific metabolites in ICB response.…”