Clinical Significance of Prognostic Alternative Splicing Signature in Tumor Immune Environment and Immune Therapy of Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) ranks the sixth prevalent tumors with high mortality globally. Alternative splicing (AS) drives protein diversity, the imbalance of which might act an important factor in tumorigenesis. We aimed to construct of AS-based prognostic signature and elucidate the role in tumor immune microenvironment (TIME) and immunotherapy in HCC.Methods: To determine the prognosis-related AS events, univariate Cox regression analysis was performed, followed by the development of prognostic signatures. The prognosis predictive ability of risk signature was validated and a predictive nomogram was constructed. To uncover the context of TIME in HCC, ESTIMATE R package, ssGSEA algorithm and CIBERSORT method and TIMER database exploration were performed. And the correlation of AS events with immune checkpoint blockade (ICB)-related genes was analyzed.Results: A total of 3294 AS events associated with survival of HCC patients were screened. Based on splicing subtypes, we then constructed eight AS prognostic signature with robust prognostic predictive accuracy. Furthermore, a quantitative nomogram exhibited robust validity in prognostic prediction of HCC. Besides, the consolidated signature was significantly correlated with TIME diversity and ICB-related genes. Finally, the splicing regulatory network uncovered the potential functions of splicing factors (SFs) in HCC.Conclusion: Herein, the AS events may contribute novel and robust indicators for the prognostic prediction of HCC. The AS-SF networks could open up new approach for investigation of potential regulatory mechanisms. And we revealed the pivotal player of AS events in context of TIME and immunotherapy, contributing to clinical decision-making and personalized prognosis monitoring of HCC.