Intratumoral microbial heterogeneity affected tumor immune microenvironment and determined clinical outcome of HBV-related HCC

Abstract

Background and Aims: The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis. Approach and Results: A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve. IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4, PIP4P2, and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data. Conclusions: Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.

Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology

“…In pituitary neuroendocrine tumors, intratumor bacteria were associated with more abundant microglia and the macrophages in nerve tissues, which further showed longitudinally branched morphology, 117 indicating the regulatory role of intratumor microbiome on macrophages. Similarly, more abundantly infiltrated M2 macrophages were detected in bacteria‐dominant subtype in HBV‐related hepatocellular carcinoma, which further showed multiple upregulated metabolism pathways 118 . Specifically, absence of beneficial bacteria with ureolytic capacity, such as Bifidobacterium , was accompanied by elevated urea cycle metabolism in colorectal tumor tissue; the urea then enter into macrophages and further skew macrophages toward a pro‐tumoral phenotype characterized by the accumulation of polyamines 119 .…”

“…Similarly, more abundantly infiltrated M2 macrophages were detected in bacteria-dominant subtype in HBV-related hepatocellular carcinoma, which further showed multiple upregulated metabolism pathways. 118 Specifically, absence of beneficial bacteria with ureolytic capacity, such as Bifidobacterium, was accompanied by elevated urea cycle metabolism in colorectal tumor tissue; the urea then enter into macrophages and further skew macrophages toward a pro-tumoral phenotype characterized by the accumulation of polyamines. 119 Gut microbiome imbalance induced by dominant colonization of E. coli promoted the expression of CTSK, which then induced M2 macrophage polarization and CRC progression.…”

Intratumoral microbiota in HCC: A new kid on the block?

“…In this case, it was fundamental to delineate whether these bacterial-dominant HCCs were somehow associated with an HCC subclass with an exhausted immune response and resistance to the available immune therapy against HCC. One thing we should also pay attention to is the lack of diversity of microbiota in HCC tumor in comparison with nontumor liver tissue, as stated by Li et al 5 If it was true, did the tumor selectively reduce certain types of microbiota for its progression? Were these microbiota “beneficial microbes” to the liver and involved in the HCC initiation and progression?…”

“…In recent years, the gut microbiome has been recognized to significantly affect HCC tumor development, 1 and bacteria have also been identified in multiple tumor types, including HCC 2–4 . However, the full spectrum of HCC tumor microbiome has remained largely unknown until Dr Li and his colleagues characterized intratumoral microbiota in HBV-related HCC through metagenomic sequencing very recently with their results published in this issue of Hepatology 5 . They proved the existence of intrinsic microbial communities in HCC as well as their potential functional relationship with HCC subtypes.…”

“…HCC microbiota on bacteria has been identified before through 16S rDNA sequencing 4 . Dr Li’s work on the characterization of the HCC microbiome globally through metagenomic sequencing further offered a missing piece to the puzzle in studying intratumoral microbiota 5 . In this study, they used 70 samples, including 29 paired nontumor and tumor tissues from patients with HCC as well as 12 liver tissues from patients with chronic hepatitis B.…”