HMGB1介导PD-1内化和降解从而增强T细胞功能的研究

Cancer is the leading cause of human death worldwide. Numerous studies have shown that the tumor microenvironment (TME) plays an important role in regulating the internal immune response of tumors. The applicant has been engaged in TME-related research for a long time, and discovered that chemotherapy induces the up-regulation of HMGB1 in doctoral phase. Further studies confirmed that there was a positive correlation between HMGB1 and IFN-r in the TME. The function of CD8+T cells was significantly increased in the group expressing high levels of HMGB1 in the TME. In addition, the expression level of PD-1 on CD8+T cells was significantly decreased after being treated with HMGB1. Therefore, it is speculated that HMGB1 can enhance the function of immune cells by down-regulating the expression of PD-1. CO-IP, immunofluorescence, flow cytometry and in vivo imaging of small animals will be used to explore the mechanism of HMGB1 regulating the expression of PD-1 in this study. In addition, we further explore the anti-tumor effect of HMGB1 on CAR-T cells by exploring the mechanism of HMGB1 enhancing the function of tumor infiltrating CD8+T cells, and lay a theoretical foundation for seeking an appropriate traditional treatment combined with immunotherapy.

在全球，肿瘤是导致人类死亡的首要原因。大量研究表明, 肿瘤微环境（tumor microenvironment，TME）在调控肿瘤内部免疫应答反应中发挥着重要的作用。申请人长期从事TME相关研究，并在博士阶段的研究中发现化疗引起HMGB1上调，进一步研究证实TME中HMGB1与IFN-r之间存在正相关，TME中HMGB1高表达组CD8+T细胞功能明显增加，此外，采用HMGB1处理CD8+T细胞后PD-1的表达水平明显下降。因此推测HMGB1可以通过下调PD-1的表达增强免疫细胞的功能。故本研究将拟采用CO-IP、免疫荧光、流式细胞术、小动物活体成像等技术分析探索HMGB1调控PD-1的机制。此外，通过探讨HMGB1增强肿瘤浸润性CD8+T细胞功能的机制，进一步探讨HMGB1促进CAR-T细胞的抗肿瘤效果，为寻求一种适当的传统治疗方法联合免疫治疗奠定理论基础。

高迁移率族蛋白B1（HMGB1）是一种危险的信号分子，已被发现可触发有效的抗肿瘤免疫反应。然而，其抗肿瘤作用的机制尚不完全清楚。在此，我们发现非小细胞肺癌（NSCLC）患者化疗诱导的HMGB1释放与CD8+T细胞PD-1表达呈负相关。体外分析表明，HMGB1可导致CD8+T细胞上PD-1表达水平显著降低。进一步的分析表明，HMGB1通过诱导肌动蛋白介导的蛋白质内化来降低PD-1的表达，进而形成早期内吞体，随后在溶酶体中降解。在异种移植模型中，HER2-CAR T细胞在HMGB1存在下功能增强。这些数据确定了HMGB1作为PD-1信号负调控因子在肺癌中的作用，HMGB1对嵌合抗原受体（CAR）T细胞的抗肿瘤作用可能为新的免疫治疗组合奠定了理论基础。