拮抗细胞凋亡抑制蛋白cIAPs通过激活NIK介导的非经典NF-κB通路增强TCR-T抗肝细胞癌研究

肝癌是全球癌症相关死亡第四大原因。CAR-T及TCR-T细胞免疫治疗成为肝癌治疗新策略。虽然CAR-T及TCR-T在血液瘤治疗中取得重大进展，但实体瘤治疗效果差强人意。实体瘤（包括肝癌）细胞免疫治疗难点在于如何逆转肿瘤逃逸。拮抗cIAPs可激活非经典NF-κB通路且非经典NF-κb通路对于维持T细胞稳态、调节肝内炎症至关重要，因此我们提出假说：拮抗cIAPs通过上调NIK激活非经典NF-κB通路增强TCR-T细胞CTL功能、使冷肿瘤变为热肿瘤打破肿瘤免疫耐受微环境，逆转肿瘤逃逸从而提高TCR-T抗肝癌效应。我们前期已构建靶向AFP的TCR-T且预实验支持上述假说。本项目拟从TCR-T细胞本身以及肝癌免疫微环境两方面研究拮抗cIAPs增强TCR-T抗肝癌的分子机制，期望发现增强TCR-T抗肝癌新靶点，为拮抗cIAPs在TCR-T治疗肝癌甚至实体瘤中的应用提供思路及理论依据。

Liver cancer is the fourth leading cause of cancer-related death worldwide. CAR-T and TCR-T immunotherapy are new strategies in the treatment of liver cancer. Although CAR-T and TCR-T have made significant progress in the treatment of hematoma, the treatment benefits of solid tumors is not satisfactory. The difficulty of immunotherapy for solid tumors (including liver cancer) is to reverse tumor escape. Antagonism of cIAPs can activate the non-canonical NF-κB pathway and non-canonical NF-κb pathway is essential for maintaining T cell homeostasis and regulating intrahepatic inflammation. Therefore, we propose a hypothesis: antagonism of cIAPs enhances the CTL function of TCR-T cells, turns cold tumors into hot tumors, breaks the tumor immunosuppression microenvironment and then reverses tumor escape and enhances the anti-liver cancer effect of TCR-T by up-regulating NIK which could activate non-canonical NF-κB pathway. We have constructed TCR-T cells targeting AFP before and preliminary experiments support the above hypothesis. This project intends to study the molecular mechanism of enhanced anti-liver cancer effect of TCR-T by antagonism of cIAPs from both the TCR-T cell itself and the liver cancer immune microenvironment. It is expected to find new targets for enhancing TCR-T against liver cancer. This study provides a theoretical basis for the application of antagonism of cIAPs in TCR-T therapies against liver cancer and even other solid tumors.