半枝莲中肿瘤免疫调节物质的发现及“Hsp90-外泌体-肿瘤免疫调控”机制的确证

肿瘤来源外泌体(TEX)是肿瘤细胞免疫应答过程中的重要调控者，其通过携带粘附分子、热休克蛋白、miRNAs等作用于受体细胞从而调节Treg等免疫细胞功能，影响肿瘤免疫应答和肿瘤微环境。本研究发现半枝莲中的活性成分野黄芩素可通过热休克蛋白90(Hsp90)负调控胰腺癌细胞外泌体释放。蛋白相互作用靶点研究显示野黄芩素并非经典的Hsp90 N端ATP结合位点抑制剂，而是靶向Hsp90 C端二聚化结构域。Hsp90 C端抑制剂的优势在于不引起热休克反应，且其所调控的Hsp90二聚化正是影响外泌体释放的机制基础。基于前期工作，本研究拟进一步确证野黄芩素靶向Hsp90 C端结构域的直接相互作用和Hsp90亚型选择性，阐明Hsp90抑制在TEX释放中的调控机制及其对肿瘤免疫的影响，从而验证本研究提出的“野黄芩素-Hsp90-外泌体-肿瘤免疫调控”的机制假说，并进一步发掘半枝莲应用于肿瘤治疗的药用价值。

Linked closely to the immune response against cancer, tumor-derived exosomes（TEX） play a key role in cancer microenvironment. TEX regulates functions of immune cells, such as Treg by carrying adhesion molecules, heat shock proteins and miRNAs to recipient cells. Our previous work found that scutellarein isolated from Scutellaria barbata D. Don, negatively regulated exosome release from pancreatic cancer cells by inhibiting heat shock protein 90. Study on binding site indicated that scutellarein targets Hsp90 C-terminal domain, instead of the classical ATP binding site in N-terminus. Without eliciting of heat shock response, the C-terminal inhibitors are considered to be superior to the N-terminal inhibitors. In addition, dimerization of Hsp90 is responsible for regulation of releasing exosomes. Based on the previous findings, in this study, we intend to elucidate the binding details of the C-terminus and verify the selectivity of scutellarein to Hsp90 subtypes, and establish the proposed mechanism of action: scutellarein - Hsp90-TEX- cancer immunotherapy, thus explore the medicinal value of Scutellaria barbata D. Don in cancer immunotherapy.