Tumor suppressor gene mutations correlate with prognosis and immunotherapy benefit in hepatocellular carcinoma

Introduction: The tumor microenvironment (TME) has profound impacts on prognosis and immunotherapy. The TME can be altered by the genomic mutations on specific tumor-suppressor genes (TSG), thus, comprehending the association between TME and TSG in hepatocellular carcinoma (HCC) is imperative. Methods: With a total of 1699 HCC patients from 6 international multicenter cohorts, we delineated the mutational landscape of TSG and summarized the proportion of TSG mutated HCC in different countries. Using the genomic and transcriptomic data, we comprehensively explored the impacts of TSG mutations on TME and immunity in HCC. A dataset of 31 HCC patients from the cBioPortal database was utilized to evaluate the predictive value of TSG subtypes for immunotherapy response. Results: Interestingly, TSG non-mutated HCC will have more "immune-hot" tumors, and display the infiltration abundance of immune cells such as B cell, CD4+/CD8+T cell, and neutrophil. Moreover, TSG non-mutated HCC was characterized by the higher expression level of three immune checkpoints, including CD40, CD40LG, and TNFRSF4. In line with the TME characterization and immune checkpoint profiles, TSG non-mutated HCC displayed prolonged overall survival and relapse-free survival, notably, are more likely to respond to immune checkpoint inhibitors. Conclusions: Our findings suggested the TSG subtypes could serve as a promising biomarker for guiding surveillance protocol and immunotherapeutic decisions for patients with HCC.