肿瘤诱导造血前体细胞分化为MDSC的调控机制

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells and myeloid progenitor cells that negatively regulate immune responses in various conditions, including chronic infectious diseases, sepsis, trauma, autoimmune diseases, transplantation and tumors. MDSC are accumulated in tumor tissues, exerting their suppressive effects and promoting disease progression. However, the nature and underlying regulatory mechanism of MDSC are still largely unknown, in particular for human. We recently observed that the composition of circulating hematopoietic stem and progenitor cells (HSPC) was significantly altered in cancer patients, exhibiting myeloid bias with a skew toward granulocytic differentiation. These myeloid precursors are selectively enriched in tumor tissues, and high levels of circulating GMP were positively correlated with disease progression. We also found that several cytokines produced by various tumors could not only promote the myeloid bias differentiation, but also induce the differentiation of myeloid precursors into functional MDSC. These findings suggest that altered circulating HSPC may serve as an important link between dysregulated bone marrow hematopoiesis and accumulated MDSC in cancer patients (PNAS, 2014; in press). Based on these findings, we will combine the clinical sample analysis and experimental studies to: 1) dissect the underlying mechanisms that regulate the proliferation and myeloid biased differentiation of HSPC in tumor bearing hosts; 2) screen and define the key factors/signaling molecules that regulate the recruitment and differentiation of HSPC into MDSCs. The results obtained from this project will not only reveal the molecular mechanisms by which tumor induce the generation of MDSC, but also provide the molecular basis for the development of MDSC as novel target for cancer prevention and cure.

髓源免疫抑制细胞（MDSC）是近年发现的一群具有未成熟分化特性以及很强免疫抑制功能的髓系细胞。在肿瘤组织中，MDSC的数量显著增加并可通过多种途径来诱导免疫耐受和疾病进展。我们新近发现：在实体瘤患者中，外周血的造血干/前体细胞（HSPC）亚群发生了髓系偏移并被招募到肿瘤组织。肿瘤来源的多种因子可诱导造血前体细胞迅速往髓系分化，并产生具有抑制功能的MDSC。提示：造血干/前体细胞的分化异常可能是肿瘤诱导MDSC产生并在组织聚集的重要因素。以此为基础，本课题拟以肠癌为模型，探讨肿瘤对HSPC增殖、分化的影响及调控机制；分析肠癌不同区域组织的趋化因子以及相应受体的表达差异，初步阐明肿瘤选择性招募髓系前体细胞的潜在机制；进一步利用体外模型，筛选并鉴定出调控髓系前体细胞分化为MDSC过程中的关键信号分子。为探讨通过调控HSPC的分化以及MDSC的产生来“恢复或重建”机体的抗肿瘤功能提供理论基础。