An Immune-inflamed Tumor Microenvironment As Defined by CD8 Score is Associated with Favorable Oncologic Outcomes in Hepatocellular Carcinoma Independent of Measures of Tumor Mutational Burden

Despite low mutational burden, immune checkpoint inhibitors have demonstrated promising results in a significant minority of hepatocellular carcinoma (HCC) patients with advanced disease. We hypothesized that HCC patients with higher levels of CD8+ T cell infiltration reflect an immune-inflamed cohort which has improved oncologic outcomes. 355 HCC patients with clinical and transcriptome data in the Cancer Genome Atlas (TCGA) and 151 HCC patients from cohort GSE7624 were analyzed. xCell computational algorithm was used to analyze immune cell infiltration in these patients. Each cohort was divided into high and low expression by the highest 2 terciles value. Gene Set Enrichment Analysis was performed to identify enriched gene sets. High CD8 score associated with improved overall survival in both cohorts (both P < 0.05). High score correlates with early BCLC stage (P = 0.035) but not AJCC stage. High CD8 also correlated with increased IFN-γ response (p = 0.038), lymphocyte infiltration (P < 0.001), and leukocyte fraction (P < 0.001). It was associated with increased polyclonality of T cell (P < 0.001) and B cell response (P = 0.017). High CD8 score correlated with increased cytolytic activity score (P < 0.001) and expression of multiple immune checkpoints including PD-1, PD-L1, CTLA-4 and Lag3 (all P < 0.001). There was no correlation to tumor mutational burden and neoantigens. GSEA demonstrated upregulation of several gene sets involved in inflammatory response and IFN-γ response. In conclusion, HCC patients with high CD8 score demonstrated favorable oncologic outcomes, which may be due to immune-mediated tumor cell attack. Furthermore, CD8 score may be a potentially useful biomarker to select patients for immune checkpoint inhibition.