TCR测序在肿瘤免疫治疗中的临床应用

doi:10.3760/cma.j.cn371439-20250312-00088

摘要/Abstract

摘要：

T细胞受体（TCR）是介导抗肿瘤免疫的关键分子，其多样性集合（即TCR组库）能够反映机体的免疫应答状态。高通量测序技术的发展极大推动了TCR组库在肿瘤免疫治疗中的应用。TCR测序在肿瘤个体化治疗中的临床价值正日益凸显。基于TCR测序分析免疫治疗应答及患者预后，对肿瘤精准治疗具有指导意义。

关键词: 免疫疗法, T细胞受体, 高通量测序

Abstract:

T cell receptor （TCR） is a key molecule mediating anti-tumor immunity， and its diversity profile （TCR repertoire） serves as a biomarker of host immune status. The development of high-throughput sequencing technologies has revolutionized the application of TCR repertoire analysis in cancer immunotherapy. The clinical value of TCR sequencing in individualized tumor treatment is increasingly prominent. Through monitoring immunotherapy response and predicting survival outcomes， TCR sequencing provides critical guidance for precision tumor therapy.

Key words: Immunotherapy, T cell receptor, High-throughput sequencing

吴学慧, 李松, 刘联. TCR测序在肿瘤免疫治疗中的临床应用[J]. 国际肿瘤学杂志, 2025, 52(8): 523-527.

Wu Xuehui, Li Song, Liu Lian. Clinical applications of TCR sequencing in cancer immunotherapy[J]. Journal of International Oncology, 2025, 52(8): 523-527.

参考文献 42

[1]	Abbott M, Ustoyev Y. Cancer and the immune system: the history and background of immunotherapy[J]. Semin Oncol Nurs, 2019, 35(5): 150923. DOI: 10.1016/j.soncn.2019.08.002.
[2]	Shah K, Al-Haidari A, Sun J, et al. T cell receptor (TCR) signaling in health and disease[J]. Signal Transduct Target Ther, 2021, 6(1): 412. DOI: 10.1038/s41392-021-00823-w.
[3]	Mahe E, Pugh T, Kamel-Reid S. T cell clonality assessment: past, present and future[J]. J Clin Pathol, 2018, 71(3): 195-200. DOI: 10.1136/jclinpath-2017-204761.
[4]	Frank ML, Lu K, Erdogan C, et al. T-cell receptor repertoire sequencing in the era of cancer immunotherapy[J]. Clin Cancer Res, 2023, 29(6): 994-1008. DOI: 10.1158/1078-0432.CCR-22-2469.
[5]	Khunger A, Rytlewski JA, Fields P, et al. The impact of CTLA-4 blockade and interferon-α on clonality of T-cell repertoire in the tumor microenvironment and peripheral blood of metastatic melanoma patients[J]. Oncoimmunology, 2019, 8(11): e1652538. DOI: 10.1080/2162402X.2019.1652538.
[6]	Joshi K, Milighetti M, Chain BM. Application of T cell receptor (TCR) repertoire analysis for the advancement of cancer immunotherapy[J]. Curr Opin Immunol, 2022, 74: 1-8. DOI: 10.1016/j.coi.2021.07.006.
[7]	Pan M, Li B. T cell receptor convergence is an indicator of antigen-specific T cell response in cancer immunotherapies[J]. Elife, 2022, 11: e81952. DOI: 10.7554/eLife.81952.
[8]	Zhang L, Cham J, Paciorek A, et al. 3D: diversity, dynamics, differential testing—a proposed pipeline for analysis of next-generation sequencing T cell repertoire data[J]. BMC Bioinformatics, 2017, 18(1): 129. DOI: 10.1186/s12859-017-1544-9.
[9]	Dong N, Moreno-Manuel A, Calabuig-Fariñas S, et al. Characterization of circulating T cell receptor repertoire provides information about clinical outcome after PD-1 blockade in advanced non-small cell lung cancer patients[J]. Cancers (Basel), 2021, 13(12): 2950. DOI: 10.3390/cancers13122950.
[10]	Chen C, Liu SYM, Chen Y, et al. Predictive value of TCR Vβ-Jβ profile for adjuvant gefitinib in EGFR mutant NSCLC from ADJUVANT-CTONG 1104 trial[J]. JCI Insight, 2022, 7(1): e152631. DOI: 10.1172/jci.insight.152631.
[11]	Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes[J]. Nat Med, 2015, 21(5): 449-456. DOI: 10.1038/nm.3850.
[12]	刘玉兰, 井海燕, 孙静, 等. 胃癌免疫治疗疗效预测及预后标志物的研究进展[J]. 国际肿瘤学杂志, 2024, 51(3): 175-180. DOI: 10.3760/cma.j.cn371439-20231109-00028.
[13]	Ji S, Li J, Chang L, et al. Peripheral blood T-cell receptor repertoire as a predictor of clinical outcomes in gastrointestinal cancer patients treated with PD-1 inhibitor[J]. Clin Transl Oncol, 2021, 23(8): 1646-1656. DOI: 10.1007/s12094-021-02562-4.
[14]	Wang X, Muzaffar J, Kirtane K, et al. T cell repertoire in peripheral blood as a potential biomarker for predicting response to concurrent cetuximab and nivolumab in head and neck squamous cell carcinoma[J]. J Immunother Cancer, 2022, 10(6): e004512. DOI: 10.1136/jitc-2022-004512.
[15]	Zhao L, Ren Y, Zhang G, et al. Single-arm study of camrelizumab plus apatinib for patients with advanced mucosal melanoma[J]. J Immunother Cancer, 2024, 12(6): e008611. DOI: 10.1136/jitc-2023-008611.
[16]	Han J, Duan J, Bai H, et al. TCR repertoire diversity of peripheral PD-1⁺CD8⁺T cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer[J]. Cancer Immunol Res, 2020, 8(1): 146-154. DOI: 10.1158/2326-6066.CIR-19-0398.
[17]	Roh W, Chen PL, Reuben A, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance[J]. Sci Transl Med, 2017, 9(379): eaah3560. DOI: 10.1126/scitranslmed.aah3560.
[18]	Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance[J]. Nature, 2014, 515(7528): 568-571. DOI: 10.1038/nature13954.
[19]	Hogan SA, Courtier A, Cheng PF, et al. Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma[J]. Cancer Immunol Res, 2019, 7(1): 77-85. DOI: 10.1158/2326-6066.CIR-18-0136.
[20]	Hopkins AC, Yarchoan M, Durham JN, et al. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma[J]. JCI Insight, 2018, 3(13): 122092. DOI: 10.1172/jci.insight.122092.
[21]	Liu W, Chen C, Li C, et al. Comprehensive analysis of immune responses to neoadjuvant immunotherapy in resectable non-small cell lung cancer[J]. Ann Surg Oncol, 2024, 31(13): 9332-9343. DOI: 10.1245/s10434-024-16053-7.
[22]	Someya M, Tokita S, Kanaseki T, et al. Combined chemoradiotherapy and programmed cell death-ligand 1 blockade leads to changes in the circulating T-cell receptor repertoire of patients with non-small-cell lung cancer[J]. Cancer Sci, 2022, 113(12): 4394-4400. DOI: 10.1111/cas.15566.
[23]	Öjlert ÅK, Nebdal D, Snapkov I, et al. Dynamic changes in the T cell receptor repertoire during treatment with radiotherapy combined with an immune checkpoint inhibitor[J]. Mol Oncol, 2021, 15(11): 2958-2968. DOI: 10.1002/1878-0261.13082.
[24]	Li Y, Zheng Y, Liu T, et al. The potential and promise for clinical application of adoptive T cell therapy in cancer[J]. J Transl Med, 2024, 22(1): 413. DOI: 10.1186/s12967-024-05206-7.
[25]	Chiffelle J, Barras D, Pétremand R, et al. Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma[J]. Immunity, 2024, 57(10): 2466-2482.e12. DOI: 10.1016/j.immuni.2024.08.014.
[26]	He J, Xiong X, Yang H, et al. Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response[J]. Cell Res, 2022, 32(6): 530-542. DOI: 10.1038/s41422-022-00627-9.
[27]	Gupta M, Wahi A, Sharma P, et al. Recent advances in cancer vaccines: challenges, achievements, and futuristic prospects[J]. Vaccines (Basel), 2022, 10(12): 2011. DOI: 10.3390/vaccines10122011.
[28]	Wang B, Peng X, Li J, et al. Personalized mRNA vaccine combined with PD-1 inhibitor therapy in a patient with advanced esophageal squamous cell carcinoma[J]. Am J Cancer Res, 2024, 14(8): 3896-3904. DOI: 10.62347/NVFB3780.
[29]	Sheikh N, Cham J, Zhang L, et al. Clonotypic diversification of intratumoral T cells following sipuleucel-T treatment in prostate cancer subjects[J]. Cancer Res, 2016, 76(13): 3711-3718. DOI: 10.1158/0008-5472.CAN-15-3173.
[30]	Yan P, Liu Y, Zhang M, et al. Reconstitution of peripheral blood T cell receptor β immune repertoire in immune checkpoint inhibitors associated myocarditis[J]. Cardiooncology, 2024, 10(1): 35. DOI: 10.1186/s40959-024-00230-4.
[31]	Lozano AX, Chaudhuri AA, Nene A, et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma[J]. Nat Med, 2022, 28(2): 353-362. DOI: 10.1038/s41591-021-01623-z.
[32]	Pai JA, Satpathy AT. High-throughput and single-cell T cell receptor sequencing technologies[J]. Nat Methods, 2021, 18(8): 881-892. DOI: 10.1038/s41592-021-01201-8.
[33]	Cui C, Tian X, Wu J, et al. T cell receptor β-chain repertoire analysis of tumor-infiltrating lymphocytes in pancreatic cancer[J]. Cancer Sci, 2019, 110(1): 61-71. DOI: 10.1111/cas.13877.
[34]	Yang H, Wang Y, Jia Z, et al. Characteristics of T-cell receptor repertoire and correlation with EGFR mutations in all stages of lung cancer[J]. Front Oncol, 2021, 11: 537735. DOI: 10.3389/fonc.2021.537735.
[35]	Shao H, Ou Y, Wang T, et al. Differences in TCR-Vβ repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age[J]. PLoS One, 2014, 9(7): e102327. DOI: 10.1371/journal.pone.0102327.
[36]	Li S, Yu W, Xie F, et al. Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer[J]. Nat Commun, 2023, 14(1): 8. DOI: 10.1038/s41467-022-35431-x.
[37]	Xie N, Shen G, Gao W, et al. Neoantigens: promising targets for cancer therapy[J]. Signal Transduct Target Ther, 2023, 8(1): 9. DOI: 10.1038/s41392-022-01270-x.
[38]	Candia M, Kratzer B, Pickl WF. On peptides and altered peptide ligands: from origin, mode of action and design to clinical application (immunotherapy)[J]. Int Arch Allergy Immunol, 2016, 170(4): 211-233. DOI: 10.1159/000448756.
[39]	Jokinen E, Huuhtanen J, Mustjoki S, et al. Predicting recognition between T cell receptors and epitopes with TCRGP[J]. PLoS Comput Biol, 2021, 17(3): e1008814. DOI: 10.1371/journal.pcbi.1008814.
[40]	Gao Y, Gao Y, Fan Y, et al. Pan-peptide meta learning for T-cell receptor-antigen binding recognition[J]. Nat Mach Intell, 2023, 5(3): 236-249. DOI: 10.1038/s42256-023-00619-3.
[41]	Feng Z, Chen J, Hai Y, et al. Sliding-attention transformer neural architecture for predicting T cell receptor-antigen-human leucocyte antigen binding[J]. Nat Mach Intell, 2024, 6(10): 1216-1230. DOI: 10.1038/s42256-024-00901-y.
[42]	Yang B, Li X, Zhang W, et al. Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis[J]. Cell Rep Med, 2022, 3(12): 100856. DOI: 10.1016/j.xcrm.2022.100856.