The heterogeneity of genomic biomarkers for immune checkpoint inhibitor in therapy-naïve primary hepatocellular carcinoma and their metachronous metastases.

Abstract

e15665 Background: Immune checkpoint blockade (ICB) has delivered unprecedented success in treating patients with metastatic cancers to extend overall survival, yet only a small percentage of patients respond. Immune-relevant genomic biomarkers, such as tumor mutation burden (TMB), neoantigen, and human leukocyte antigen class I (HLA-I) are emerging as potential predictors for immunotherapy response. However, little is known about their heterogeneity in metastatic cancer patients. In this study, we aim to characterize these immune-relevant genomic biomarkers in primary and matched metastatic hepatocellular carcinoma (HCC). Methods: Two cohorts of samples were included in this study. Cohort 1: a total of 24 pairs of surgical resected primary and matched metastatic HCC tissue. Cohort 2: 29 surgical resected primary HCC tissue from patients with long-term relapse-free survival. All samples were characterized using whole exome sequencing and RNA sequencing. We compared TMB, neoantigen and HLA-I genotype between primary and matched metastatic tumors, as well as between primary tumors with or without postoperative metastatic relapse. Results: The TMB of primary HCC with metastatic relapse was significantly higher than that with long-term relapse-free survival (Mean, 32 vs 17 mutations/Mb, P< 0.05), while neoantigen and HLA-I genotype failed to show statistical difference. Paired comparison between primary and matched metastatic tumors indicated that both TMB and neoantigen were significantly decreased in metastases ( P< 0.05). We further categorized metastases into two subgroups based on their HLA-I genotype. HLA-I homozygosity in at least one locus (homozygous) occurred in 9 metastases, while the rest metastases showed maximal heterozygosity at HLA-loci (heterozygous). HLA-I heterozygous metastases were associated with significantly higher neoantigen load compared with HLA-I homozygous metastases ( P< 0.05). Conclusions: High TMB might be a poor prognostic factor in patients with resected HCC and a potential predictor for postoperative adjuvant therapy with ICB. Metastatic HCC showed lower antigenicity than the corresponding primary tumors. Therefore, they might not show the same responsiveness to immunotherapy as primary tumor did. However, our HLA-I genotype analysis provides evidence that HLA-I heterozygosity has potential implication for predicting response of metastatic HCC to ICB.