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Gut microbiota plays a pivotal role in the pathogenesis of hepatocellular cancer (HCC), significantly affecting the HCC treatment. It has been reported that the HCC patients’ response to the immunotherapy of PD-1/PD-L1 blockade was associated with their gut microbiota profiles. However, the impact of gut microbiota on anti-HCC immunity and its underlying mechanism are poorly understood. Treating HCC-bearing mice with a specific and non-hepatotoxic antibiotic cocktail caused the increased relative abundance of specific commensal bacteria such as Bacteroides, resulting in suppression of HCC growth and development which was involved in the activation of intrahepatic antitumor immune responses. Gut microbiota recolonization of Bacteroides thetaiotaomicron (B. th) in gut-sterilized HCC-bearing mice significantly improved the therapeutic efficacy of anti-PD-1 antibody (αPD-1 Ab) against HCC. Fecal microbiota transplantation (FMT) from HCC patients who received and responded to αPD-1 Ab treatment improved the efficacy of αPD-1 Ab treatment against HCC in mice model. Mechanistic studies demonstrated that the modulation of Krüppel-like factor 2 (KLF2)/Toll-like receptor 9 (TLR9) signaling and the accumulation of CpG-enriched genomic DNAs of B. th in livers/tumors activated the tumor antigen-specific CD8+ T cells through the dendritic cell in a TLR9-dependent manner. In conclusion, gut microbiota as a causative factor can be targeted to improve anti-HCC immunotherapy. Citation Format: Xiaogiang Qi, Ming Yang, Lixin Ma, Jonathan Mitchem, Jussuf Kaifi, Shiyou Chen, Aaron Ericsson, Eric Kimchi, Kevin Staveley-O’Carroll, Guangfu Li. Modulating gut microbiota to improve intrahepatic immunity against hepatocellular cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4116. |
