Profiling of Hepatocellular Carcinoma Neoantigens Reveals Immune Microenvironment and Clonal Evolution Related Patterns

Abstract

Background: Neoantigens derived from tumor specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of HCC neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully addressed. Methods: We integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explore its interactions with tumor clonal evolution, driver mutations and immune microenvironments. Findings: Besides the observation that higher somatic neoantigen load indicated a better clinical outcome in HCC, it is important that we discovered two subgroups with distinct neoantigen expression pattern, which exhibited markedly different features including tumor clonal evolution states, microsatellite instability as well as clinical outcomes. Gene set enrichment analysis revealed that upregulation of MYC and its targets could suppress immune responses and elevate neoantigen expression in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We also observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. We also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets for HCC in future. Interpretation: Our results revealed the landscape of HCC neoantigens and discovered two clinically relevant subgroups with distinct neoantigen expression patterns, suggesting the neoantigen expression should be fully considered in future immunotherapeutic interventions. Funding Statement: This work was supported by the National Science and Technology Major Project of China (grant No.2018ZX10302205), the Science and Technology Development Project of Central government Guiding Local Government (Grant No. 2017L3017, Grant No. 2018L3016, Grant No. 2019L3027), the Scientific Foundation of Fujian Province (Grant No.2018J01145), the Scientific Foundation of Fujian Health and family planning Department (Grant No. 2019-ZQN87), the Joint Funds for the Innovation of Science and Technology of Fujian Province (Grant No. 2018Y9121). Declaration of Interests: All authors declare no competing interests related to this study. Ethics Approval Statement: All human sample collection and the usage of human samples were approved by the Institution Review Board of Mengchao Hepatobiliary Hospital of Fujian Medical University and were conducted according to the principles of the Declaration of Helsinki. Written informed consent was obtained from the enrolled patient.