联合阻断免疫检查点Tim-3与PD-1在化疗耐药绒癌中的抗肿瘤作用及机制研究

绒癌是发生在育龄女性的高度恶性肿瘤，尽管对化疗敏感，但仍有部分绒癌对化疗产生耐药，目前尚无有效的治疗手段。因此，对于耐药绒癌患者，亟需新的治疗方法。免疫检查点抑制剂成为肿瘤免疫治疗的新方法。本课题组前期研究发现，免疫检查点Tim-3/Gal-9及PD-1/PD-L1在化疗耐药绒癌标本中高表达，联合阻断Tim-3与PD-1增强了T细胞对化疗耐药绒癌细胞系的杀伤能力。我们提出以下科学假说：化疗耐药绒癌中高表达的Tim-3/Gal-9及PD-1/PD-L1抑制T细胞的功能，联合阻断Tim-3与PD-1可恢复T细胞功能，杀伤耐药绒癌细胞。本项目拟利用临床标本明确Tim-3在绒癌中的意义；建立免疫系统人源化的化疗耐药绒癌小鼠模型，在体内及体外实验中利用抗体联合阻断免疫检查点Tim-3与PD-1，恢复T细胞功能，杀伤绒癌细胞，发挥抗肿瘤作用，为化疗耐药绒癌的免疫治疗提供新的实验室依据和治疗策略。

Choriocarcinoma is a highly malignant tumor that occurs in women of childbearing age. Although it is sensitive to chemotherapy, some choriocarcinomas are resistant to chemotherapy. and no effective treatment are available. Therefore, chemotherapy-resistant choriocarcinoma requires new treatments. Immune checkpoint inhibitors have become a new approach to cancer immunotherapy. Our previous study found that immune checkpoints Tim-3/Gal-9 and PD-1/PD-L1 were highly expressed in chemotherapy-resistant choriocarcinoma specimens, and combined blocking of Tim-3 and PD-1 enhanced the killing ability of T cells against chemotherapy-resistant choriocarcinoma cell lines. We propose the following scientific hypothesis: Tim-3/Gal-9 and PD-1/PD-L1, which are highly expressed in chemotherapy-resistant choriocarcinoma, inhibit T cell function, and combined blocking of Tim-3 and PD-1 can restore T cell function, thereby killing resistant choriocarcinoma cells. This project intends to use clinical specimens to clarify the significance of Tim-3 in choriocarcinoma; and establish the immune system humanized chemotherapy-resistant choriocarcinoma mouse models, and block the immune checkpoint Tim-3 with PD-1 to restore T cell function and to kill chemotherapy-resistant choriocarcinoma cells, and thus exerting anti-tumor effects in vivo and in vitro experiments. Thereby, this will provide new laboratory basis and treatment strategy for immunotherapy of chemotherapy-resistant choriocarcinoma.