靶向AFP T细胞受体(TCR)库的构建及记忆性TCR-T抗肝细胞癌研究

肝癌是中国第三大肿瘤致死原因，尚无有效疗法。TCR-T在实体瘤治疗中取得令人瞩目的成果。70-80%的肝细胞癌（HCC）重新表达AFP，AFP可作为HCC过继细胞治疗的靶点。获得高特异性及多样性T细胞受体（TCR）是TCR-T的基础及难点，目前尚无针对AFP的TCR-T产品批准上市。目前TCR-T治疗存在以下问题：1.传统方法获得的TCR亲和力较低或者多样性较差而无足够的候选TCR；2.TCR-T体内难以长期存活导致肿瘤复发。我们以往研究克隆及鉴定3对靶向AFP功能性TCR、证明TCR信号参与疫苗诱导的记忆性干细胞样T细胞的形成从而增强抗肿瘤效应。本研究以无人类自身抗原耐受的鼠源TCR为切入点，构建靶向AFP的HLA-A24限制性TCR库并从记忆性TCR-T角度研究TCR亲和力与TCR-T长期抗肝细胞癌效应关系，为指导靶向AFP的TCR-T疗法提供依据，具有重要的理论及实际意义。

Liver cancer represents the third most common cause of cancer related death in china and there is no effective therapy. The TCR-T has made remarkable achievements in the solid tumor treatment. 70-80% of hepatocellular carcinoma (HCC) re-express AFP, so AFP could serve as a target for HCC adoptive transfer therapy. To obtain high specificity and diversity of T cell receptor (TCR) is the basis and difficulty of TCR-T therapy, no TCR-T products against AFP are currently approved. At present, TCR-T treatment has the following problems: 1. TCRs obtained by the traditional method have low affinity or poor diversity, therefor there are no enough candidate TCRs; 2. Difficulty to survive long-term of TCR-T leads to tumor recurrence in vivo. In previous studies, we cloned and identified 3 pairs of functional TCRs against AFP and proved TCR signaling was involved in vaccine-induced stem cell-like memory T cells which enhanced antitumor effects. In this study, murine TCRs without human self-antigen tolerance were used to construct the HLA-A24-restricted TCR library targeting human AFP; Relationship between TCR affinity and long-term anti-hepatocellular carcinoma effect of TCR-T was studied from the perspective of memory TCR-T. This study will provide the basis for guiding the TCR-T therapy targeting AFP and has important theoretical and practical significance.