new research Uncovers Link Between T-Cell exhaustion, Viral Integration & Aggressive Liver Cancer
BOSTON, MA - A comprehensive multi-omics study has revealed critical insights into the complex interplay between T-cell exhaustion, hepatitis B virus (HBV) integration, and the advancement of hepatocellular carcinoma (HCC), the most common type of liver cancer. Researchers identified distinct exhaustion profiles within the tumor microenvironment (TIME) and linked high T-cell exhaustion to increased viral integration, aggressive proliferation subtypes, and heightened oncogenic potential. The findings, published today, pave the way for personalized therapies targeting immune exhaustion in virus-related HCC.
The study, utilizing whole-exome, transcriptome, and single-cell sequencing, categorized patients into high and low exhaustion groups based on effector CD8+ T cell marker expression. The high-exhaustion group (n=2 in the initial cohort, n=28 in a validation cohort) demonstrated significantly higher clonal expansion of CD8+ T cells (Gini index: 0.83 vs. 0.48, p* = 0.006) alongside increased sharing of weary effector memory and cycling T cells.This group also exhibited expanded populations of CD4+ regulatory T cells and follicular helper T cells with elevated PDCD1 expression,alongside increased *TP53 mutation rates and proliferation subtype signature scores. Conversely,the low-exhaustion group (n=6 initially,n=78 in validation) predominantly harbored TERT mutations. Critically, the high-exhaustion group showed more pronounced HBV integrations, elevated intrahepatic covalently closed circular DNA (cccDNA) and pregenomic (pg)RNA levels – indicators of active viral replication – and stronger proliferation subtype signatures.
This research is particularly meaningful as HCC is a leading cause of cancer-related death worldwide, with a substantial proportion of cases linked to chronic HBV infection. Understanding the mechanisms driving tumor development in these patients is crucial for improving treatment outcomes. The study’s identification of a strong association between high HBV integration,T-cell exhaustion,and aggressive proliferation subtypes offers a potential new avenue for therapeutic intervention. Researchers believe these findings establish a foundation for developing personalized therapies tailored to the immune-exhaustion status within the TIME of each HCC patient, perhaps improving response rates and long-term survival.