Tyro3和CDK9激酶介导PD-1抑制剂耐药的分子机制和开发新型癌症免疫联合疗法的研究

肿瘤细胞利用PD-1和PD-L1的结合来逃逸免疫监察，其抑制剂临床应用是近年来肿瘤治疗的革命性进展。临床上，三阴性乳腺癌(TNBC)几乎没有有效的治疗方案，而PD-1抑制剂已被初步证实对10%的TNBC患者具有疗效，但对病患生存率的改善还无法令人满意；临床数据显示PD-1抑制剂会出现耐药性。我们前期研究新发现：利用TNBC耐药细胞株筛选找到Tyro3和CDK9两个激酶可能是造成PD-1抑制剂耐药的主要原因。本项目将进一步利用临床标本、多种体外功能试验和小鼠乳腺癌动物模型来阐释其详细的分子机制，验证Tyro3和CDK9激酶是否能作为预测PD-1抑制剂耐药的肿瘤标志物；利用小分子药物库筛选新的Tyro3和CDK9抑制剂，并测试激酶抑制剂与PD-1抑制剂的联合疗法是否能在临床上克服PD-1抑制剂的耐药性问题。项目的成功实施将为开展耐药肿瘤的精准联合免疫疗法的临床试验提供坚实的科学依据。

Cancer cells can escape immune surveillance via the interaction between PD-1 and PD-L1. Their inhibitors are revolutionary used in clinical cancer immunotherapy in recent years. Clinically, triple-negative breast cancer (TNBC) has almost no effective treatments, and PD-1 inhibitors have been initially shown to be effective in 10% of TNBC patients, but the improvement in patient survival has not been satisfactory. Importantly, some clinical data had shown that PD-1 inhibitors could develop resistance. A new finding from our previous research: we have performed a non-bias shRNA screening in TNBC-resistant cell lines to get two intracellular Tyro3 and CDK9 kinases, which may involve in the resistance of PD-1 inhibitors. This proposal will further use clinical specimens, in vitro functional tests, and mouse breast cancer animal models to reveal its detailed molecular mechanism and verify whether Tyro3 and CDK9 kinases can be used as tumor biomarkers to predict the resistance of PD-1 inhibitors. The small-molecule drug library will be used to screen new Tyro3 and CDK9 inhibitors, and these kinase inhibitors in combination with PD-1 inhibitors are also to be tested whether they could overcome the resistance of PD-1 inhibitors clinically. The successful implementation of the project will provide a solid scientific basis for the clinical trials of precision combined immunotherapy for PD1-resistant tumors.