A Novel Therapeutic Strategy for Hepatocellular Carcinoma Targeting Telomerase Reverse Transcriptase

Background: Hepatocellular carcinoma (HCC) arises from genetic alterations, including telomerase reverse transcriptase (TERT) mutations. Despite advances in tyrosine kinase and immune checkpoint inhibitors, TERT remains undruggable. Given the high prevalence of TERT promoter mutations, targeting TERT offers a promising therapeutic strategy.
Methods: Immune responses to the HLA-A24-binding TERT peptide (VYGFVRACL) in HCC patient lymphocytes were assessed via IFNg ELISpot assay. The TERT peptide vaccine was evaluated as an adjuvant to radiofrequency ablation. Antigen-specific T cells were analyzed by single-cell RNA sequencing and T cell receptor (TCR) profiling. TCR-transduced T cells were functionally tested in vitro and in vivo.
Results: Genomic profiling of 59 HCC patients showed TERT promoter mutations in 57% (34/59). Positive immune responses to the TERT peptide were observed in 3 of 31 (10%) HCC cases but none in 11 healthy controls or 29 chronic hepatitis patients. The TERT peptide induced immune responses in 8 of 14 cases (57%), and TERT-specific T cells exhibited a memory phenotype with IL7R and NOSIP expression. The TERT-specific TCR A12.78 conferred specificity to TERT-expressing cancer cells, enabling in vitro HepG2 killing and delayed tumor growth in HepG2-engrafted NSG mice.
Conclusion: TERT-targeted immunotherapy offers a potential alternative for HCC treatment.