MDSC在肝脏与肠道肿瘤中聚集和功能的差异及其调控机制

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.

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。

髓源免疫抑制性细胞（Myeloid-derived suppressor cells，MDSC）是一群具有未成熟特性以及免疫抑制功能的异质细胞，在肿瘤和炎症等多种疾病的进展和转归过程中起着重要作用。但关于MDSC在人体肿瘤组织以及外周免疫器官中的组成、聚集与调控机制尚不清楚。我们发现：1、肿瘤通过诱导脾脏髓外造血来产生髓系抑制细胞的新机制：肝脏肿瘤可显著增强脾脏从外周血中募集造血干/前体细胞（HSPC）的能力，通过CCL2/CCR2趋化轴招募特定HSPC亚群，并在脾脏基质影响下通过“重编程”HSPC来产生具有更强免疫抑制功能的MDSC，去除脾脏髓外造血可显著增强anti-PD-L1治疗的效果。此外，我们在多种实体瘤患者的脾脏中，均观察到髓外造血升高的现象。2、肠道和肝脏肿瘤中MDSC的组成差异及其调控机制：鉴定出了肿瘤组织中的早期MDSC亚群，阐明维甲酸是肠道肿瘤中MDSC产生和抑制功能发挥的重要物质基础。3、肿瘤微环境可通过调控代谢重编程来促进MDSC产生和功能：MDSC的发育和功能都依赖于糖酵解途径的保障，谷氨酰胺代谢为MDSC在糖胁迫条件下的重要补偿途径。4、鉴定出多个在组织中起着促/抗肿瘤作用的Mφ新亚群以及对肝癌进展的调控机制：如肝癌中促肿瘤进展的c-Met+Mφ亚群能通过促进自分泌MMP9来促进肿瘤转移，肝癌组织中的Mo/Mφ产生TNF-a，上调内皮细胞CXCR4表达，从而促进肿瘤血管生成；此外，肿瘤活化单核细胞分泌的TNF-α和IL-1β能够通过诱导侵袭前沿区域癌细胞自噬水平的上调来促进肿瘤转移。而具有抗肿瘤活性的CD169+Mφ亚群能通过促进Th1/Tc1来产生抗肿瘤效应。上述结果说明：肿瘤一方面可从源头上通过调控机体的造血系统，诱导造血干/祖细胞发生髓系偏移和功能改变，并成为组织中MDSC的重要来源；而在肿瘤组织中，还可通过调控代谢重编程来促进MDSC产生和功能发挥。这些结果为进一步探讨器官肿瘤微环境对髓系细胞分化与功能的调控机制提供了新的思路，也为肿瘤免疫治疗提供新的干预靶点。相关结果已有8篇论文发表在J. Clin. Invest., Autophagy和J. Pathol.等知名刊物。