免疫检查点蛋白VISTA对乳腺癌免疫微环境的调控机制及其小分子抑制剂的发现研究

目前，针对三阴性乳腺癌（TNBC）尚无有效的靶向药物治疗手段，而现有的免疫检查点抑制剂对乳腺癌（包括TNBC）免疫治疗的反应率又非常低。因此，发现和确证乳腺癌（尤其是TNBC）免疫逃逸新机制和新靶标进而开发新的免疫治疗药物具有重要的理论研究意义和临床应用价值。前期研究发现新型免疫检查点VISTA在乳腺癌（尤其是TNBC）的免疫微环境中显著表达，且与临床预后具有一定相关性，然而，相关的分子机制尚不清楚。本项目将在分子、细胞共培养、动物模型及临床样本水平上深入探讨VISTA在乳腺癌免疫微环境中的定位、表达及调控机制，重点关注在巨噬细胞中表达的VISTA对肿瘤浸润T细胞及其TCR信号通路的调控作用及分子机制。此外，结合结构生物学和人工智能辅助虚拟筛选等研究手段进行VISTA小分子抑制剂的发现研究。本项目期望为基于VISTA阻断的乳腺癌免疫治疗提供理论依据、新的生物标志物、新靶标和新型先导化合物。

Currently, there is no effective molecularly targeted therapy for triple-negative breast cancer (TNBC), and the response rate following current immune checkpoint blockade therapy is very low for breast cancer including TNBC. Therefore, it is of great importance in terms of theoretical research and clinical utility to disclose and identify novel pathways and targets for immune escape of breast cancer (especially TNBC). Our previous studies found that new immune checkpoint VISTA was significantly expressed in breast cancer (especially TNBC) immune microenvironment, and was correlated with the clinical prognosis. However, the underlying molecular mechanism is unclear. In this project we will investigate the location, expression and modulatory mechanism of VISTA in breast cancer immune microenvironment, with more focus on the effects and action mechanism of VISTA expressed in macrophage in regulating tumor-infiltrating T cells and TCR signaling pathway. Additionally, with the aids of structural biology and artificial intelligence based virtual screening, we will identify novel VISTA small molecule inhibitors. We wish to provide theoretical evidence, new biomarkers and novel targets for VISTA blockade based immune therapy for breast cancer.