CK1ε调控T细胞PD1蛋白的稳定性在抗肿瘤免疫中的作用研究

近年来，PD1/PD-L1抗体治疗肿瘤取得了迅猛的发展，然而仅有少数实体瘤患者获益，因此需要更深入的研究来解决所面临的的问题。酪蛋白激酶CK1和肿瘤的发生发展密切相关，但CK1是否调节抗肿瘤免疫未见报道。前期研究发现B16F10细胞在条件性敲除T细胞CK1ε基因的小鼠皮下的生长速度明显比野生型小鼠缓慢，提示CK1ε可能参与抗肿瘤免疫；初步机制表明CK1ε能与PD1互作并增加PD1蛋白的稳定性。本研究将进一步深入研究CK1ε调控PD1蛋白稳定性的分子机制，并探索参与此过程的E3泛素连接酶；着重探讨CK1ε-PD1信号在CD8+ T细胞抗肿瘤免疫中的作用，揭示肿瘤病人CD8+ T细胞中CK1ε与PD1表达的相关性，并在小鼠体内评价CK1抑制剂和抗PD1抗体联用在肿瘤治疗中的疗效。本项目的预期成果将首次揭示并阐明CK1ε参与抗肿瘤免疫的作用及分子机制，为今后抗肿瘤免疫疗法提供新的思路和途径。

In recent years, great progress has been made in treatment of tumor using anti-PD1/PD-L1 antibody, but only a few proportion of solid tumor patients benefit from anti-PD1/PD-L1 therapy, therefore, more in-depth studies are needed to solve these problems. Casein kinase 1 (CK1) is closely related to the initiation and development of tumor, but whether CK1 regulates anti-tumor immunity has not been reported. Our previous studies showed that when subcutaneous injection of B16F10 cells into mice, tumor grew more slowly in mice with conditionally CK1ε knockout in T cells than wild-type mice, which indicated that CK1ε may be involved in regulation of anti-tumor immunity. Mechanically, CK1ε could interact with PD1 and increase the protein stability of PD1. In this study, we will further study the molecular mechanism of CK1ε regulating the protein stability of PD1, and explore the E3 ubiquitin ligase which may be involved in this process. We will focus on the effect of CK1ε-PD1 signaling in regulation of the anti-tumor immunity of CD8+ T cells, reveal the expression relevance of CK1ε and PD1 in CD8+ T cells from patients, and evaluate the anti-tumor effect of combination of CK1 inhibitor and anti-PD1 antibody in mice. This project will reveal and clarify the role and molecular mechanism of CK1ε in anti-tumor immunity for the first time, and provide new ideas and approaches for cancer immunotherapy in the future.