Hepatitis B virus‐related hepatocellular carcinoma exhibits distinct intratumoral microbiota and immune microenvironment signatures

Abstract Emerging evidence supports a high prevalence of cancer type‐specific microbiota residing within tumor tissues. The intratumoral microbiome in hepatocellular carcinoma (HCC), especially in viral (hepatitis B virus [HBV]/hepatitis C virus [HCV]) HCC, has not been well characterized for their existence, composition, distribution, and biological functions. We report herein a finding of specific microbial signature in viral HCC as compared to non‐HBV/non‐HCV (NBNC) HCC. However, the significantly diverse tumor microbiome was only observed in HBV‐related HCC, and Cutibacterium was identified as the representative taxa biomarker. Biological function of the unique tumor microbiota in modulating tumor microenvironment (TME) was characterized by using formalin‐fixed paraffin‐embedded (FFPE) tissue‐based multiplex immunofluorescence histochemistry (mIFH) allowing simultaneous in situ detection of the liver cancer cells surrounded with high/low density of microbiota, and the infiltrating immune cells. In HBV_HCC, the intratumoral microbiota are positively associated with increased tumor‐infiltrating CD8+ T lymphocytes, but not the CD56+ NK cells. Two subtypes of myeloid‐derived suppressor cells (MDSCs): monocytic MDSCs and polymorphonuclear MDSCs, were also found to be positively correlated with the intratumoral microbiota in HBV_HCC, indicating an inhibitory role of these microbial species in antitumor immunity and the contribution to the liver TME in combination of chronic viral hepatitis during HCC development.