Targeting a tolerogenic HLA-G genotype to tackle immune evasion and adaptive resistance in HBV-driven HCC

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BACKGROUND & AIMS: HBV-associated hepatocellular carcinoma (HCC) is characterized by immune evasion and heterogeneous responses to immunotherapy. However, the mechanisms driving tumor-immune tolerance and their impact on checkpoint inhibitor-based therapies remain poorly understood. To address this gap, we generated a patient-derived HBV-induced HCC cell line that preserves a clinically relevant immune evasion mechanism mediated by human leukocyte antigen G (HLA-G) expression. METHODS: We performed whole-exome sequencing on two spatially separated tumor regions to define genomic signatures with emphasis on the HLA-G locus. Patient-derived tumor cells were modified using upcyte® technology, generating the up-LC14A1 cell line. Molecular stratification included an in-house HCC cohort (n = 13), healthy donors (n = 4), serum samples from early-stage liver disease (n = 4), diagnosed HCC (n = 10), and global datasets (TCGA biopsies, n = 24; HCC, n = 120). Functional characterization included NK92 co-culture assays (1:1, 1:5, 1:10) and orthotopic transplantation in mice (HUH7, n = 3; Hep3B, n = 4; HepG2H1.3, n = 4; up-LC14A1, n = 14). RESULTS: Whole-exome sequencing revealed a clonally coherent HCC carrying an HLA-G 3'UTR haplotype associated with immune tolerance. Cohort stratification confirmed elevated soluble HLA-G in patient #14. The derived up-LC14A1 line retained hepatobiliary and viral features and showed stable proliferation with low-level HBV DNA production. Transcriptomic profiling positioned up-LC14A1 within the HCC landscape. In vivo, orthotopic transplantation generated structured liver tumors and prolonged survival compared with immortalized HCC lines. The up-LC14A1 cell line resisted NK92 cytotoxicity through dynamic HLA-G induction, while HLA-G silencing restored immune killing and induced compensatory PD-L1 expression. CONCLUSIONS: The up-LC14A1 model represents a patient-derived HBV-HCC system capturing a clonally stable but dynamically regulated HLA-G-mediated immune-tolerant state. This platform enables mechanistic investigation of immune escape and provides a translational model for testing targeted immunotherapies in HBV-associated HCC. IMPACT AND IMPLICATIONS: HBV-associated HCC exhibits a profound immune evasion capacity and an insufficient response to immunotherapy. Nevertheless, preclinical models that mimic viral persistence and tumor resistance are underrepresented. The immune modulatory molecule HLA-G has emerged as a potent target for immunotherapy in HCCs owing to its direct suppression of T and NK cells. Here, we established a novel patient-derived HBV-HCC cell line (up-LC14A1) that mediates immune evasion via HLA-G upregulation.

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