IGF1下调微环境TAMs膜表面IFN-γR2在黑色素瘤靶向治疗耐药中的分子机制研究

靶向治疗耐药是制约BRAF突变黑色素瘤临床疗效的关键因素，成为临床上亟待解决的问题。肿瘤耐药标志物有助于临床开展靶向与免疫联合治疗试验。目前研究认为肿瘤微环境参与耐药的发生，并且肿瘤相关巨噬细胞（TAMs）被认为具有促进肿瘤的作用。我们在前期研究中发现微环境IGF1通过调控内皮细胞行为参与血管重构。此外，TAMs也表达IGF1R，我们认为IGF1可能以旁分泌方式作用于TAMs，并介导TAMs膜表面IFN-γR2下调，进而影响TAMs功能，促进耐药。本项目拟采用细胞共培养等方式在细胞水平和动物模型中研究肿瘤源性IGF1对TAMs功能的影响，探讨IGF1介导的肿瘤细胞与TAMs交互作用导致耐药的分子机制；同时，我们将收集肿瘤病人的组织和血清样本，分析血清IGF1在临床治疗监测的意义。通过本课题的实施，有望阐明微环境IGF1调控TAMs导致肿瘤耐药的机制，明确IGF1作为耐药标志物的临床价值。

Targeted therapy resistance is a key factor restricting the clinical efficacy of BRAF mutant melanoma, and it has become an urgent clinical problem. Tumor drug resistance markers are helpful to launch clinical trials about combination of targeted therapy and immunotherapy. Current studies believe that the complex tumor microenvironment is involved in the development of drug resistance, and tumor-associated macrophages (TAMs) are believed to have a tumor-promoting effect. In our previous studies, we found that IGF1, the secreted protein in the microenvironment, participates in vascular remodeling by regulating the behavior of endothelial cells. In addition, TAMs also express IGF1R. We believe that IGF1 may act on TAMs in a paracrine manner and mediate the down-regulation of IFNγ-R2 on the membrane surface of TAMs, thereby affecting the function of TAMs and promoting drug resistance. This project intends to use methods including cell co-culture to study the effect of tumor-derived IGF1 on the function of TAMs at the cellular level and in animal models, and to explore the molecular mechanism of drug resistance caused by the interaction of tumor cells and TAMs mediated by IGF1; at the same time, we will collect the tissue and serum samples of tumor patients to identify the clinical significance of serum IGF1 in the aspect of treatment monitoring. Through the implementation of this project, it is expected to clarify the mechanism of microenvironmental IGF1 regulating TAMs leading to tumor drug resistance, and to clarify the clinical value of IGF1 as a drug resistance marker.