Gut microbiota modulation potentiates anti-tumor immunity and immunotherapy in hepatocellular carcinoma 2308568

Abstract

Abstract Introduction The gut microbiota functions as a critical extrinsic regulator along the gut-liver axis, shaping hepatocarcinogenesis and anti-tumor immunity and therapy. However, the specific microbial determinants and mechanisms underlying these effects remain incompletely defined. Methods Motivated by the observed impact of gut microbiota on anti-PD-1 therapeutic efficacy in hepatocellular carcinoma (HCC) patients, we employed our unique and clinically relevant mouse HCC models to comprehensively characterize tumor-associated microbial signatures using 16S rRNA gene sequencing. Application of a non-hepatotoxic antibiotic cocktail 3 (ABX-3), targeted microbial supplementation, and recolonization with selected bacterial species following gut sterilization with ABX-5 enabled us to delineate the causal relationship between microbiota modulation, intrahepatic immune activation, and immunotherapeutic responses. Results Bacteroides-enriched gut microbiota derived from anti-PD-1 responder HCC patients significantly suppressed HCC growth in our mouse model. In parallel, ABX-3 administration, implemented as both a preventive and therapeutic intervention, attenuated tumor initiation and progression by selectively enriching specific gut bacterial taxa. Functionally, ABX-3 enhanced tumor antigen-specific T cell activation and boosted intrahepatic anti-tumor immunity via microbial remodeling. Among enriched taxa, Bacteroides thetaiotaomicron (B.th) emerged as a key microbial effector driving these immunomodulatory and anti-tumor effects. These findings prompted further investigation into additional enriched microbial members with the capacity to activate hepatic immunity and potentiate immunotherapy either individually or combination with B.th. Conclusion ABX-3-mediated modulation of gut microbiota promotes robust intrahepatic anti-HCC immune activation. Identifying microbial species with ability to enhance hepatic immune responses provides a foundation for developing microbiome-based immunotherapeutic strategy for HCC. Funding Source National Institutes of Health (NIH) R01CA274959, R01CA250536, R01 DK130340, R01CA208396; partly supported by VA merit Award I01 BX004065-1. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)