Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma

  • Cancer Biol Med. 2025 Apr 9;22(4):412-432. doi: 10.20892/j.issn.2095-3941.2024.0434.
Fang Liu  1  2  3 ,  Hua Chen  4 ,  Suxin Wu  1  2  3 ,  Chenlu Zhu  1  2  3 ,  Mingji Zhang  3  5 ,  Wei Rui  4 ,  Dong Zhou  3  5 ,  Yang Wang  2  3 ,  Xin Lin  4 ,  Xueqiang Zhao  4 ,  Yunbin Ye  2  3
Affiliations
  • 1. School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
  • 2. Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China.
  • 3. Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
  • 4. School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 5. The Department of Hepatopancreatobiliary Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China.
PMID: 40205806 DOI: 10.20892/j.issn.2095-3941.2024.0434
Abstract

Objective: The 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.

Methods: A 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.

Results: Ten 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.

Conclusions: This preclinical study demonstrated the beneficial effects of neoepitope BTLAP267L-specific TCR-T cell immunotherapy, unlocking a novel strategy for personalized precision therapy in HCC.

Keywords
Neoepitope; T cell receptor-T cell; hepatocellular carcinoma; immunotherapy.
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