Kalinina Anastasiia, Persiyantseva Nadezda, Britanova Olga, Lupyr Ksenia, Shagina Irina, Khromykh Ludmila, Kazansky Dmitry
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Kashirskoe sh. 24, 115478 Moscow, Russian Federation.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya st. 16/10, 117997 Moscow, Russian Federation.
Comput Struct Biotechnol J. 2023 May 26;21:3196-3209. doi: 10.1016/j.csbj.2023.05.028. eCollection 2023.
T cell engineering with T cell receptors (TCR) specific to tumor antigens has become a breakthrough towards personalized cancer adoptive cell immunotherapy. However, the search for therapeutic TCRs is often challenging, and effective strategies are strongly required for the identification and enrichment of tumor-specific T cells that express TCRs with superior functional characteristics. Using an experimental mouse tumor model, we studied sequential changes in TCR repertoire features of T cells involved in the primary and secondary immune responses to allogeneic tumor antigens. In-depth bioinformatics analysis of TCR repertoires showed differences in reactivated memory T cells compared to primarily activated effectors. After cognate antigen re-encounter, memory cells were enriched with clonotypes that express α-chain TCR with high potential cross-reactivity and enhanced strength of interaction with both MHC and docked peptides. Our findings suggest that functionally true memory T cells could be a better source of therapeutic TCRs for adoptive cell therapy. No marked changes were observed in the physicochemical characteristics of TCRβ in reactivated memory clonotypes, indicative of the dominant role of TCRα in the secondary allogeneic immune response. The results of this study could further contribute to the development of TCR-modified T cell products based on the phenomenon of TCR chain centricity.
利用针对肿瘤抗原的T细胞受体（TCR）进行T细胞工程改造，已成为个性化癌症过继性细胞免疫疗法的一项突破。然而，寻找治疗性TCR往往具有挑战性，因此迫切需要有效的策略来鉴定和富集表达具有优异功能特性TCR的肿瘤特异性T细胞。我们使用实验性小鼠肿瘤模型，研究了参与对同种异体肿瘤抗原的初次和二次免疫反应的T细胞TCR库特征的连续变化。对TCR库的深入生物信息学分析表明，与主要活化的效应细胞相比，重新活化的记忆T细胞存在差异。在再次遇到同源抗原后，记忆细胞富含表达具有高潜在交叉反应性α链TCR的克隆型，并且与MHC和对接肽的相互作用强度增强。我们的研究结果表明，功能上真正的记忆T细胞可能是过继性细胞疗法中治疗性TCR的更好来源。在重新活化的记忆克隆型中，未观察到TCRβ理化特性的明显变化，这表明TCRα在二次同种异体免疫反应中起主导作用。这项研究的结果可能会基于TCR链中心性现象，进一步推动TCR修饰的T细胞产品的开发。
