IRF7对肿瘤中G-MDSC分化的调控作用及病理意义研究

Myeloid-derived suppressor cells (MDSCs) play critical role in the induction of tumor immunotolerance. MDSCs can be further classified into two distinct subsets, granulocytic (G-MDSCs) and monocytic (M-MDSCs). Interestingly, 70-80% MDSCs in tumor-bearing hosts are G-MDSCs. However, the mechanisms regulating the development of MDSC subsets, remains poorly understood. In our preliminary study, we found that a close association exists between IRF7 and the development of tumor-derived G-MDSC. The experimental evidence includes: IRF7 expression was significantly down-regulated in tumor-derived G-MDSCs, when compared with the correponding cells from naive mice; IRF7 knockout tumor mice displayed systematic G-MDSC expansion, as well as enhanced tumor metastasis; Overexpression of IRF7 suppressed G-MDSC differentiation from bone marrow in vitro; G-MDSCs levels were negatively correlated with IRF7 expression in clinical hepatic carcinoma patients. Based on these observations, we propose that IRF7 may represent a novel negative regulator of G-MDSCs development in tumor. Aim to test this possibility, we will: Study the effect of tumor-derived cytokines on IRF7 expression in G-MDSC; Investigate the role of IRF7 in G-MDSCs development; Determine the transcriptional target of IRF7 in G-MDSCs and the regulatory mechanism; Demonstrate the pathological significance of IRF7-mediated G-MDSCs development in both tumor-bearing mice and clinical cancer patients. The implementation of this proposal will uncover a novel mechanism dictating G-MDSC development in cancer, and will also provide potential therapeutic target for MDSC-based immunotherapy.

髓系抑制性细胞（MDSC)是肿瘤免疫耐受的重要参与者，肿瘤个体中70-80%的MDSC为粒细胞型G-MDSC。但G-MDSC分化调控的机制尚待阐明。我们前期发现：IRF7与肿瘤中G-MDSC分化密切相关。实验依据包括：荷瘤小鼠来源的G-MDSC中IRF7表达水平显著下调；IRF7基因缺失小鼠体内存在G-MDSC异常扩增，伴随肿瘤转移增加；过表达IRF7可显著抑制G-MDSC体外分化；肝癌患者外周血中G-MDSC比例与IRF7表达呈负相关。据此提出“IRF7是肿瘤中G-MDSC分化的负性调控因子”。为验证此假说：拟首先研究肿瘤来源细胞因子对G-MDSC中IRF7表达的调控作用，利用体内及体外实验研究IRF7对G-MDSC分化的调控作用及其分子机制，最后利用荷瘤小鼠及临床肿瘤患者样品对其其病理意义进行研究。项目将揭示肿瘤中G-MDSC分化调控的新机制，为基于MDSC的肿瘤免疫治疗提供新靶标。

髓系抑制性细胞（MDSC)是肿瘤免疫耐受的重要参与者，肿瘤个体中70-80%的MDSC为粒细胞型G-MDSC。但G-MDSC分化调控的机制尚待阐明。我们前期发现：IRF7与肿瘤中G-MDSC分化密切相关。实验依据包括：荷瘤小鼠来源的G-MDSC中IRF7表达水平显著下调；IRF7基因缺失小鼠体内存在G-MDSC异常扩增，伴随肿瘤转移增加；过表达IRF7可显著抑制G-MDSC体外分化；肝癌患者外周血中G-MDSC比例与IRF7表达呈负相关。据此提出“IRF7是肿瘤中G-MDSC分化的负性调控因子”。为验证此假说：拟首先研究肿瘤来源细胞因子对G-MDSC中IRF7表达的调控作用，利用体内及体外实验研究IRF7对G-MDSC分化的调控作用及其分子机制，最后利用荷瘤小鼠及临床肿瘤患者样品对其其病理意义进行研究。项目将揭示肿瘤中G-MDSC分化调控的新机制，为基于MDSC的肿瘤免疫治疗提供新靶标。