HLA-DR⁺ Tumor Cells Show an Association with a Distinct Immune Microenvironment and CD8⁺ T-Cell Exhaustion in...

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with hepatitis B virus (HBV) as a major driver. Despite the pivotal role of viral infections in shaping the tumor microenvironment (TME), the mechanistic differences among HBV-, hepatitis C virus (HCV)-, and non-B non-C (NBNC)-associated HCC remain poorly understood. By integrating the largest publicly available single-cell RNA sequencing (scRNA-seq) dataset of HCC (160 samples from 124 patients) with multi-scale protein-level validation using multiplex immunofluorescence and tissue microarrays (198 HCC specimens), HLA-DR⁺ tumor cells are identified as a distinctive feature of HBV⁺HCC. These tumor cells uniquely express MHC class II molecules, typically restricted to antigen-presenting cells, and correlate with immune checkpoint activation and PD-L1 expression, potentially contributing to an immunosuppressive microenvironment specific to HBV⁺HCC. Trajectory analysis revealed distinct CD8⁺ T-cell differentiation pathways in HBV⁺HCC, characterized by enhanced exhaustion and stem-like phenotypes. HLA-DR⁺ tumor cells are associated with increased recruitment of CD8⁺ T cells and correlated with T-cell exhaustion, potentially contributing to a suppressive TME. Clinically, high proportions of HLA-DR⁺ tumor cells are linked to poor survival outcomes, especially when accompanied by elevated PD-L1 expression, suggesting that HLA-DR⁺ tumor cells may serve as a potential predictive biomarker for immunotherapy efficacy in HCC. Collectively, the findings highlight HLA-DR⁺ tumor cells as a distinctive feature of HBV-associated HCC (HBV⁺HCC), providing novel insights into possible immunosuppressive mechanisms and therapeutic targets for immunotherapy in this disease context.