Genomic analysis quantifies pyroptosis in the immune microenvironment of HBV-related hepatocellular carcinoma

Abstract

Pyroptosis, a way of pro-inflammatory death, plays a significant part in the tumor microenvironment (TME). A recent study has shown that the hepatitis C virus changes the TME by inducing pyroptosis against hepatocellular carcinoma (HCC). However, compared to TME in hepatitis C virus-infected HCC, the exploration of immune characteristics and response to immunotherapy associated with the pyroptosis phenotype is still insufficient in hepatitis B virus-related HCC (HBV-HCC). Our study constructed pyroptosis-score (PYS) via principal-component analysis (PCA) to unveil the link between pyroptosis and tumor immunity in 369 HBV-HCC patients. Compared with the low-PYS group, subjects with higher PYS were associated with poor prognosis but were more susceptible to anti-PD-L1 treatment. In addition, we found that PYS can serve independently as a prognostic factor for HBV-HCC, making it possible for us to identify specific small molecule drugs with a potential value in inhibiting tumors via targeting pyroptosis. Also, the target genes predicted by the Weighted gene co-expression network analysis (WGCNA) and pharmacophore model were enriched in the HIF-1 signaling pathway and NF-kB transcription factor activity, which were related to the mechanism of inflammation-driven cancer. The PYS is extremely important in predicting prognosis and responses to immunotherapy. New treatment strategies for inflammation-driven cancers may be found by targeting pyroptosis.

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 .…”

Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review)

“…Among them, SOR is a multi-target kinase inhibitor that directly modulates immunity, causing HCC cell death by inducing macrophage pyroptosis and activating cytotoxic NK cells ( 41 ). A study has found that the pyroptosis-score (PYS) could be used to assess the prognosis of patients with HCC due to hepatitis B virus (HBV-HCC), as a higher PYS in patients with HBV-HCC was associated with a worse prognosis, and these patients were more likely to receive anti-PD-L1 therapy ( 178 ). In addition, a risk score model related to pyroptosis can be constructed to predict the prognosis and immunological characteristics of HCC ( 38 ).…”

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

“…[2][3][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. Although there are many fundamental questions yet to be answered about these microbes in HCC, the presence of intratumoral microbiota in the HCC tumor ecosystem has shed light on a new research direction of HCC basic and translational studies.…”

“…[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. A broad spectrum of microbiota was identified in these tissues, that is, 13 phyla, 15 classes, 31 orders, 39 families, 58 genera, and 107 species.…”

“…[9] In this case, it was fundamental to delineate whether these bacterialdominant 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?…”