Identification of cell senescence molecular subtypes in prediction of the prognosis and immunotherapy of hepatitis B virus-related hepatocellular carcinoma

Hepatitis B virus (HBV)-infected hepatocellular carcinoma (HCC) has a high incidence and fatality rate worldwide, being among the most prevalent cancers. The growing body of data indicating cellular senescence (CS) to be a critical factor in hepatocarcinogenesis. The predictive value of CS in HBV-related HCC and its role in the immune microenvironment are unknown. To determine the cellular senescence profile of HBV-related HCC and its role in shaping the immune microenvironment, this study employed a rigorous evaluation of multiple datasets encompassing 793 HBV-related HCC samples. Two novel distinct CS subtypes were first identified by nonnegative matrix factorization, and we found that the senescence-activated subgroup had the worst prognosis and correlated with cancer progression. C1 and C2 were identified as the senescence-suppressed and senescence-activated subgroups. The immune microenvironment indicated that C2 exhibited a relatively low immune status, higher tumor purity, and lower immune scores and estimated scores, while the C1 subgroup possessed a better prognosis. The CS score signature based on five genes (CENPA, EZH2, G6PD, HDAC1, and PRPF19) was established using univariate Cox regression and the lasso method. ICGC-LIRI and GSE14520 cohorts were used to validate the reliability of the CS scoring system. In addition, we examined the association between the risk score and hallmark pathways through gene set variation analysis and gene set enrichment analysis. The results revealed a high CS score to be associated with the activation of cell senescence-related pathways. The CS score and other clinical features were combined to generate a CS dynamic nomogram with a better predictive capacity for OS at 1, 2, and 3 years than other clinical parameters. Our study demonstrated that cellular senescence patterns play a non-negligible role in shaping the characteristics of the immune microenvironment and profoundly affecting tumor prognosis. The results of this study will help predict patient prognosis more accurately and may assist in development of personalized immunotherapy for HBV-related HCC patients.