KIT基因变异调控黑色素瘤免疫微环境的分子机制及治疗策略研究

KIT基因编码一种受体酪氨酸激酶，其变异仅见于小部分欧美人群黑色素瘤中，却是我国黑色素瘤极为重要的驱动基因。申请人前期研究发现，KIT变异黑色素瘤免疫细胞浸润情况与正常组存在显著差异，CD8+T细胞比例显著下降，且存在β-catenin通路活性增加；而KIT抑制剂伊马替尼可增加肿瘤内CD8+T细胞的浸润。在此基础上，申请人拟利用特色临床资源，结合体内外实验明确KIT基因变异对黑色素瘤免疫微环境的影响，解析KIT基因变异抑制T细胞作用的分子机制；并创建多种动物模型，揭示伊马替尼靶向黑色素瘤细胞外的免疫调节作用，探索KIT抑制剂与免疫检查点阻断剂的最佳联合用药方式。以期阐明KIT基因变异在黑色素瘤中的免疫编辑作用，为制定适合于KIT变异黑色素瘤患者的治疗策略提供理论依据。

KIT encodes a receptor tyrosine kinase, its variation is rare in Caucasion melanoma, however, it’s a very important driver gene in Chinese melanoma. We compared the tumor immune infiltration signature between KIT variated and normal melanoma, and found that the CD8+ T cell infiltration was significantly reduced in melanomas with KIT variation. Furthermore, the β-catenin pathway was upregulated in KIT variated melanoma. Through humanized NSG mouse model, we demonstrated that imatinib could increase CD8+ T cell infiltration in melanoma with KIT variation. On this basis, we aim to take advantage of the clinical resources to investigate the effects of KIT variation on the immune microenvironment of melanoma, and the molecular mechanism of KIT variation in inhibiting the function of effector T cells through in vitro and in vivo studies. We will further establish multiple mouse models to discover the off-target immune regulation effects of imatinib in melanoma, and the combined therapeutic strategy with immune checkpoint inhibitor. This project will clarify the immunoediting effect of KIT variation in melanoma, and provide theoretical basis for the treatment of melanoma patients harboring KIT variations.