IRF4调控c-Myc表达对肿瘤中髓系抑制性细胞分化的影响及机制研究

Individual tumor immunosuppression status is the key to limiting antitumor immune response. Myeloid-derived suppressor cell (MDSC) is one of the most important reasons of inducing immune suppression, targeted MDSC was considered as a emerging target for tumor immunotherapy. However, the mechanisms regulating the development of MDSC remain poorly understood. Recent study and our preliminary data showed that IRF4 is a key regulator of MDSC development in tumorgensis. We found out that MDSC in IRF4 KO tumor-bearing mice increased significantly, and c-Myc expression was significantly lower in IRF4 KO-MDSC. Meanwhile, overexpression of c-Myc can reduce the level of MDSC. Therefore, we hypothsis that IRF4 may affect the differentiation of myeloid cells by transcriptional regulation of its target gene c-Myc, thus induce MDSC accumulation and promote tumor development. Hence, this project intends to study the molecular mechanisms of IRF4 transcriptional regulates c-Myc in tumor-derived MDSC by some experiment including Luciferase, ChiP assay. To clarify the regulation effect of c-Myc on MDSC differentiation, experiments including in vitro signal block and overexpression and adoptive transfer will be applied. Eventually goal of this project is that affirm the predictive value of IRF4 - c-Myc - MDSC "axis" in tumor recurrence and metastasis and provide accurate target for the prevention of tumor immunotherapy.

肿瘤个体免疫抑制状态是限制抗肿瘤免疫应答的关键。髓系抑制性细胞（MDSC）是诱导机体免疫抑制的重要原因，靶向MDSC被认为是肿瘤免疫治疗的新兴靶点。但肿瘤诱导MDSC增多的具体机制尚未明确。现有研究及本项目预试验证实：IRF4是调控肿瘤中MDSC分化聚集的关键因子。我们发现在IRF4 KO小鼠中MDSC显著增多，且MDSC中c-Myc表达显著下调；同时过表达c-Myc可降低MDSC的水平。由此，我们推论IRF4可通过转录调控c-Myc表达来影响髓系细胞分化，诱导MDSC增多，进而促进肿瘤转移。据此，本项目拟通过Luciferase，ChiP等实验研究IRF4调控c-Myc表达的具体分子机制，进一步通过体外信号阻滞,过表达及过继转移等实验明确c-Myc对MDSC分化的调控作用,最终明确“IRF4-c-Myc-MDSC”这条“轴”对肿瘤患者复发转移的预测价值,为肿瘤免疫治疗提供潜在的干预靶点。

肿瘤个体免疫抑制状态是限制抗肿瘤免疫应答的关键。髓系抑制性细胞（MDSCs）是诱导机体免疫抑制的重要原因，MDSCs的积累是增强抗肿瘤免疫应答和肿瘤免疫治疗成功的主要障碍之一。因此，靶向MDSC被认为是肿瘤免疫治疗的新兴靶点。肿瘤宿主中的MDSCs主要是多形核细胞(PMN-MDSCs)。然而，肿瘤诱导MDSC增多的具体机制仍未完全明确。在本项目中，我们发现干扰素调节因子4 (IRF4)在PMN-MDSCs的发展中起关键作用，但在单核细胞来源的MDSCs（M-MDSCs）的分化中没有明显作用。在肿瘤小鼠模型中，IRF4的缺失导致PMN-MDSCs显著升高，并且能增强PMN-MDSCs的抑制活性，从而促进小鼠体内肿瘤的生长和转移。进一步机制研究表明，转录因子IRF4可转录调控c-Myc基因的表达。c-Myc的过表达几乎消除了IRF4缺失在PMN-MDSCs发育中的影响。重要的是，在临床癌症患者中，IRF4表达水平与PMN-MDSCs的数量和肿瘤的发展呈负相关，但与c-Myc的表达呈正相关。综上，本研究表明IRF4是肿瘤中PMN-MDSCs分化发育过程中的一种新的调控因子，可能对肿瘤的进展有预测价值，为肿瘤免疫治疗提供潜在的干预靶点。