A novel pyroptosis-regulated gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma

Background: Pyroptosis, a newly discovered type of programmed cell death, has both anti-tumor and tumor-promoting effects on carcinogenesis. In hepatocellular carcinoma (HCC), however, the associations between pyroptosis-regulated genes and prognosis, immune microenvironment, and immunotherapy response remain unclear. Samples and methods: Sequencing data were collected from The Cancer Genome Atlas database, The International Cancer Genome Consortium (ICGC), and The Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). First, we investigated the expression levels and copy number variations (CNVs) of 56 pyroptosis genes in HCC and pan-cancer. Next, we identified 614 genes related to 56 pyroptosis-associated genes at the expression, mutation, and CNVs levels. Pathway enrichment analysis of 614 genes in the Hallmark, KEGG, and Reactome databases yielded a total of 253 significant signaling pathways. The pyroptosis-regulated genes (PRGs) comprised 108 genes that were derived from the top 20 signaling pathways, of which 57 genes had prognostic value in HCC. The least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for PRGs with prognostic values. Ultimately, we constructed a risk score model with seven PRGs to predict HCC prognosis and validated its predictive value in three independent HCC cohorts. Risk scores were used to illustrate receiver operating characteristic (ROC) curves predicting 1, 3, and 5-years overall survival (OS). Single-sample gene set enrichment analysis (ssGSEA), was performed to study 28 types of immune cells infiltrated in HCC. The relationship between the risk signature and six immune checkpoint genes and immunotherapy was analyzed. Results: A total of seven PRGs were obtained following multiple screening steps. The risk score model containing seven PRGs was found to correlate significantly with the HCC prognosis of the training group. In addition, we validated the risk score model in two additional HCC cohorts. The risk score significantly correlated with infiltrating immune cells (i. e. CD4(+) T cells, etc.), ICB key molecules (i. e. HAVCR2, etc.), and ICB response. Conclusions: This study demonstrated a vital role of PRGs in predicting the prognosis and immunotherapy response of HCC patients. The risk model could pave the way for drugs targeting pyroptosis and immune checkpoints in HCC.