我们在前期已观察到：在肝癌和消化道肿瘤组织中，多种免疫细胞或因子可呈现出各自独特的表型与分布，并对疾病进展起着不同甚至相反的作用。MDSC是一群具有未成熟特性与很强免疫抑制功能的髓系细胞。我们新近发现：在肝癌和胃肠道等多种实体瘤患者中，其外周血的造血干/前体细胞亚群均发生了相似的髓系偏移现象，是肿瘤诱导MDSC产生的重要因素。但是在肠癌组织浸润免疫细胞中，髓系前体细胞所占的比例约比肝癌组织高50倍。提示：这两类器官的组织微环境很可能影响了髓系前体细胞或/和MDSC在这些区域的聚集和功能。本课题拟结合临床样本检测和实验模型，来系统的研究/比较：髓系前体细胞以及MDSC在肝脏与肠道肿瘤中聚集、组成与功能的差异与调控机制；筛选并鉴定出可显著影响肠癌进展/退化的关键细胞亚群或功能分子；并探讨选择性调控MSDC在组织中聚集与分化的可行性以及对肿瘤进展的影响；为肿瘤免疫治疗提供新的思路和干预靶点。

We and others have previously shown that the infiltrated immune cells and cytokines could exhibit distinct phenotype and distribution patterns in human tumors originated from liver and digestive tract, and thus have differential or even opposing impact on disease progression. These findings suggest that distinct composition or tissue micro-environments from these tissue/organs may contribute to the formation and shape of immune milieu. 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. We recently observed that the composition of hematopoietic stem and progenitor cells (HSPC) was significantly altered and exhibited a similar myeloid bias in peripheral blood from patients with different types of tumors including liver and digestive tract carcinomas. These myeloid precursors are selectively enriched in tumor tissues, and may serve as an important link between dysregulated bone marrow hematopoiesis and accumulated MDSC in cancer patients. Interestingly, the frequency of infiltrated myeloid precursors in colorectal cancer was 50 times higher than those in HCC tissues. These results indicate that the local conditions from these two organs may influence the accumulation and functional programs of myeloid precursors and/or MDSCs. Based on these findings, we will combine the clinical sample analysis and experimental studies to: 1) characterize the accumulation, composition and functional activities of myeloid precursors and MDSCs in both liver cancer and colorectal tumor tissues, and dissect the underlying mechanisms; 2) screen and define the key subsets and signaling molecules that may have significant impact on the progression or degeneration of colorectal cancer; 3) evaluate the effectiveness on tumor progression by selectively regulating the recruitment and differentiation of MDSCs in colorectal tumor tissues. 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.