Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma
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...
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2025-04-01
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| Series: | Cancer Biology & Medicine |
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| Online Access: | https://www.cancerbiomed.org/content/22/4/412 |
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| author | Fang Liu Hua Chen Suxin Wu Chenlu Zhu Mingji Zhang Wei Rui Dong Zhou Yang Wang Xin Lin Xueqiang Zhao Yunbin Ye |
| author_facet | Fang Liu Hua Chen Suxin Wu Chenlu Zhu Mingji Zhang Wei Rui Dong Zhou Yang Wang Xin Lin Xueqiang Zhao Yunbin Ye |
| author_sort | Fang Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-04442d98461c4e9a97ca21f3b4e5c516 |
| institution | Kabale University |
| issn | 2095-3941 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj-art-04442d98461c4e9a97ca21f3b4e5c5162025-08-20T03:53:42ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412025-04-0122441243210.20892/j.issn.2095-3941.2024.0434Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinomaFang Liu0Hua Chen1Suxin Wu2Chenlu Zhu3Mingji Zhang4Wei Rui5Dong Zhou6Yang Wang7Xin Lin8Xueqiang Zhao9Yunbin Ye10School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaSchool of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaSchool of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaSchool of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaFujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, ChinaSchool of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaFujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, ChinaLaboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaSchool of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaSchool of Basic Medical Sciences, Tsinghua University, Beijing 100084, ChinaLaboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaObjective: 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.https://www.cancerbiomed.org/content/22/4/412neoepitopet cell receptor-t cellimmunotherapyhepatocellular carcinoma |
| spellingShingle | Fang Liu Hua Chen Suxin Wu Chenlu Zhu Mingji Zhang Wei Rui Dong Zhou Yang Wang Xin Lin Xueqiang Zhao Yunbin Ye Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma Cancer Biology & Medicine neoepitope t cell receptor-t cell immunotherapy hepatocellular carcinoma |
| title | Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma |
| title_full | Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma |
| title_fullStr | Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma |
| title_full_unstemmed | Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma |
| title_short | Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma |
| title_sort | neoepitope btlap267l specific tcr t cell immunotherapy unlocks precision treatment for hepatocellular carcinoma |
| topic | neoepitope t cell receptor-t cell immunotherapy hepatocellular carcinoma |
| url | https://www.cancerbiomed.org/content/22/4/412 |
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