荷瘤状态下MDSC来源的新机制--- S100A8介导脾脏红系前体细胞分化受阻并分化成MDSC

The abnormal increase of MDSC in tumor bearing state is one of the important factors of anti-tumor immune deficiency, elucidation the molecular mechanism is the prerequisite for designing a novel anti-tumor immunotherapy. Based on our previous research findings that a block in erythroid differentiation leading to anemia, the blocked erythroid cells can further differentiate into MDSC under the tumor condition. Combined with the konwledge from the publication, we proposed: tumor bearing state causes erythroid differentiation defect may be mediated by S100A8 through the activation of p53 signaling pathway, interaction with TLR-4 and RAGE contribute to generation of inflammatory cytokines and ROS, to further differentiate into MDSC cells, this may be the mechanism of abnormal increase of MDSC under tumor condition. In the present, we will determine the effect of tumor bearing state on erythroid and MDSC differentiation through the establishment of tumor-bearing mice models and analyzing the correlation of anemia state and MDSC amount. Moreover, we will explore the underlying mechanisms of erythroid differentiation defect and further differentiate into MDSC. Through this project, we could elucidate the specific causes of anemia and anti-tumor immune deficiency in clinical tumor patients, more importantly it will provide some clues to the design of novel anti-tumor immunotherapy.

荷瘤状态下髓源性抑制细胞（MDSC）异常增多是抗瘤免疫应答缺陷重要因素之一，因此阐明其来源及分化机制是设计新的抗瘤免疫治疗方案的基础和前提。申请者基于前期研究发现，荷瘤状态下红系分化障碍导致贫血，受阻红细胞最终分化成为MDSC；并结合相关文献支持，提出科学假说：在荷瘤状态下S100A8可能通过活化P53信号通路介导红系细胞分化受阻，通过与TLR-4及RAGE结合诱导炎性因子分泌及ROS的产生使其最终分化成为MDSC，可能是荷瘤状态下MDSC异常增多的分子机制之一。本项目拟通过建立不同的荷瘤模型，结合临床样本分析，明确荷瘤状态对红系分化及其最终分化成MDSC的现象；利用条件性基因敲除鼠和抗体阻断性实验，阐明荷瘤状态下S100A8介导红系分化障碍及其向MDSC分化的作用和机制。通过本项目的研究，有望深入理解临床肿瘤患者合并贫血及免疫功能低下的具体原因，而且也将为肿瘤免疫治疗方案设计提供新思路。

荷瘤状态下髓源性抑制细胞（MDSC）异常增多是抗瘤免疫应答缺陷重要因素之一，因此阐明其来源及分化机制是设计新的抗瘤免疫治疗方案的基础和前提。申请者基于前期研究发现，荷瘤状态下红系分化障碍导致贫血，受阻红细胞最终分化成为MDSC；并结合相关文献支持，提出科学假说：在荷瘤状态下S100A8可能通过活化P53信号通路介导红系细胞分化受阻，通过与TLR-4及RAGE结合诱导炎性因子分泌及ROS的产生使其最终分化成为MDSC，可能是荷瘤状态下MDSC异常增多的分子机制之一。本项目通过建立不同的荷瘤模型，结合临床样本分析，明确了荷瘤状态对红系分化及其最终分化成MDSC的现象并阐明了荷瘤状态下红系分化障碍及其向MDSC分化的作用和机制。通过本项目的研究，为临床肿瘤患者合并贫血及免疫功能低下的临床现象提供了科学解释，也为设计肿瘤免疫治疗策略提供了新思路。