以T细胞受体为基础的免疫疗法研究进展

T cell receptor-based immunotherapy: a review

摘要:

T细胞是机体抗肿瘤免疫的核心，以T细胞功能调控为基础的免疫检查点疗法已经在多种肿瘤的临床治疗中取得了重大突破，以基因工程化T细胞为基础的过继性免疫细胞疗法在血液瘤治疗中取得了重要进展，免疫治疗已经对肿瘤的临床治疗产生了深刻变革，成为肿瘤临床治疗策略的重要组成部分。T细胞受体（T cell receptor，TCR）赋予了T细胞识别肿瘤抗原的特异性，能够识别由主要组织相容性复合体（major histocompatibility complex，MHC）呈递的包括胞内抗原在内的广泛肿瘤抗原，具有高度的抗原敏感性，因而具有广泛的抗肿瘤应用前景。2022年第一款TCR药物的上市开启了TCR药物开发的新纪元，多项TCR药物临床研究表现出潜在的肿瘤治疗价值。本文综述了以TCR为基础的免疫治疗策略研究进展，包括T细胞受体工程化T细胞（T cell receptor-engineered T cell，TCR-T）和TCR蛋白药物，以及基于TCR信号的其他免疫细胞疗法，以期为以TCR为基础的免疫治疗策略开发提供参考。

关键词:T细胞受体;免疫治疗;T细胞受体工程化T细胞;T细胞衔接器

Abstract:

T cells play central roles in anti-tumor immune responses. Immune checkpoint therapy, which is based on modulation of T cell reactivity, has achieved breakthrough in clinical treatment of multiple tumors. Moreover, adoptive T cell therapy, which includes mainly genetically engineered T cells, has shown substantial treatment efficacy in hematoma. Immune therapy has tremendously changed the scenario of clinical tumor treatment and become critical strategies for treating multiple tumors. T cell receptor (TCR) is the fundamental molecule responsible for the specificity of T cell recognition. TCRs could recognize peptides, which are derived from intracellular or extracellular tumor antigens, presented by major histocompatibility complex (MHC) and are therefore highly sensitive to low antigen level. Thereby, TCRs are broadly recognized as promising molecules for the development of anti-tumor drugs. The approval of the first TCR drug in 2022 has initiated a new era for TCR-based therapeutics and since then, multiple TCR drugs have shown substantial treatment efficacy in multiple tumors. This review summarizes the progress of TCR-based immune therapeutic strategies, including T cell receptor-engineered T cell (TCR-T), TCR-based protein drugs, and other cell therapies based on TCR signaling, providing useful information for future design of immune therapeutics based on TCR.

Key words:T cell receptor;immunotherapy;T cell receptor-engineered T cell;T cell engager