@article{Liu2025, 
author = {Fang Liu and Hua Chen and Suxin Wu and Chenlu Zhu and Mingji Zhang and Wei Rui and Dong Zhou and Yang Wang and Xin Lin and Xueqiang Zhao and Yunbin Ye},
title = {Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma},
year = {2025},
journal = {Cancer Biology & Medicine},
volume = {22},
number = {4},
pages = {412-432},
keywords = {Neoepitope, T cell receptor-T cell, immunotherapy, hepatocellular carcinoma},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2024.0434},
doi = {10.20892/j.issn.2095-3941.2024.0434},
abstract = {ObjectiveThe high heterogeneity of hepatocellular carcinoma (HCC) renders traditional therapies unable to effectively activate the patient’s immune system to combat tumors. Patients with advanced HCC and T cell functional deficiencies may benefit more from cellular immunotherapy, especially tumor neoepitope-targeted T cell receptor (TCR)-T cells. Neoepitopes with strong immunogenicity provide precise targets for HCC, further enhancing the efficacy of cellular immunotherapy.MethodsA scalable workflow for identifying neoepitopes from 7 HLA-A*02:01-restricted patients with HCC was established based on whole exome sequencing and bioinformatics analyses, followed by identification of neoepitope-specific TCRs through tetramer-based screening and single-cell TCR cloning technology, which were further validated in the JC4 cell model. The cytotoxicity of CD8+ TCR-T cells was evaluated in neoepitope-positive tumor cell lines or NCG mice.ResultsTen specific neoepitopes were identified, among which neoepitope B and T lymphocyte attenuatorP267L [BTLAP267L (SLNHSVIGL)] exhibited advantageous properties as a potential tumor target. Three TCRs (85-3, 126-5, and 52-3) were confirmed to specifically recognize the neoepitope BTLAP267L, while no cross-recognition of irrelevant or wild-type epitopes was observed. Activated BTLAP267L-specific CD8+ TCR-T cells released extensive perforin, granzyme B, IFN-γ, and TNF-α in vitro, thereby inducing strong cytotoxic effects against BTLAP267L-positive T2 or HCC cell lines. BTLAP267L-specific CD8+ TCR-T cells mediated robust tumor regression due to long-lasting survival and released perforin without causing significant cytotoxic effects on normal organs in murine experiments.ConclusionsThis preclinical study demonstrated the beneficial effects of neoepitope BTLAP267L-specific TCR-T cell immunotherapy, unlocking a novel strategy for personalized precision therapy in HCC.}
}