S100A9介导骨髓微环境PD-1/PD-L1信号参与MDS免疫逃逸机制研究

MSC免疫调节功能紊乱参与MDS发生发展。研究表明S100A9/TLR4信号是MDS炎性致病共同通路, 但在MSC中的作用尚不清楚。申请人发现：S100A9可诱导MSC发生衰老，伴免疫抑制功能增强；S100A9作用于MSC后，PD-L1的表达增加，MMP1下调；体外下调MSC MMP1促进了MDS增殖；MDS-MSC中 PD-L1表达与MMP1负相关。我们推测S100A9下调MMP1的表达，促进MSC PD-L1分泌，介导T淋巴细胞耐受，参与MDS免疫逃逸。为验证这一假说，我们将采用WB、FCM、RNA干扰、基因芯片、CHIP等手段，从分子、细胞、动物模型层面探讨S100A9诱导的MSC免疫功能改变，明确其介导的MMPs-PD-L1信号调控MSC免疫功能的分子机制。本研究将从MDS-MSC介导免疫逃逸这个新视点为揭示MDS发病机制奠定基础，为MDS免疫治疗提供新的证据。

Immune regulatory dysfunction of MSC is involved in the development of MDS.Studies have shown that S100A9/TLR4 signaling is a common pathway of MDS inflammatory pathogenesis, but its role in MSC is still unclear.The applicant found that S100A9 could induce the senescence of MSC with enhanced immunosuppressive function.After the action of S100A9 on MSC, the expression of pd-l1 was increased and MMP1 was down-regulated.In vitro down-regulation of MSC MMP1 promoted MDS proliferation.The expression of pd-l1 in MDS-MSC was negatively correlated with MMP1.We speculated that S100A9 down-regulated MMP1 expression, promoted the secretion of MSC pd-l1, mediated T lymphocyte tolerance, and participated in MDS immune escape.In order to test this hypothesis, we will explore the changes in MSC immune function induced by S100A9 from the level of molecules, cells and animal models by WB, FCM, RNA interference, gene CHIP, CHIP, etc., and clarify the molecular mechanism of MMPs-PD-L1 signal in regulating the immune function of MSC.This study will lay a foundation for revealing the pathogenesis of MDS from the new perspective of mds-msc-mediated immune escape and provide new evidence for MDS immunotherapy.