肿瘤可通过诱导免疫耐受抑制机体免疫应答，从而逃避免疫监视。我们的近期研究表明，B16肿瘤细胞可诱导MDSC在小鼠肝脏中聚集，进而抑制ConA诱发的NK T细胞介导的肝损伤，而肿瘤细胞产生的TGF-β1在其中发挥重要作用。本项目拟在此基础上深入探讨肿瘤诱导的肝脏免疫耐受的分子机制，尤其是肿瘤产生的TGF-β1在肿瘤诱导肝脏免疫耐受中的作用，以及肿瘤诱导聚集在肝脏中的MDSC对肝脏NK T细胞的调控机制。关键科学问题：1、肿瘤细胞究竟如何诱导肝脏免疫耐受？发挥主要免疫抑制作用的细胞是哪一群？2、肿瘤来源的TGF-β1在这个过程中发挥怎样的调控作用？3、肿瘤诱导聚集在肝脏中的MDSC如何调控肝脏NK T细胞功能？分子机制如何？通过这些问题的探讨，希望在肿瘤诱导肝脏免疫耐受的机制、肿瘤诱导的MDSC对肝脏NK T细胞的作用机制等方面有所突破，并为针对肿瘤诱导的免疫耐受的免疫治疗提供一些新的思路。

Tumor can inhibit the immune response of the host and escape from the immune surveillance by inducing immune tolerance. Our recent work indicated that B16 melanoma cells could induce the accumulation of MDSC in the liver of mice and suppress ConA induced NK T cells mediated liver injury. The tumor-derived TGF-β1 played an important role in this process. In the current proposal, we will further explore the molecular mechanism of tumor induced immune tolerance in liver. We will focus on the role of tumor-derived TGF-β1 in tumor induced immune tolerance and the regulatory mechanism of tumor induced MDSC on NK T cells in liver. In this propose, we will address our scientific questions with the following specific aims: 1) How do the tumor cells induce immune tolerance in liver? Which population of immune cells are more important in the immune tolerance function in liver? 2) Function of tumor-derived TGF-β1 in the tumor induced immune tolerance in liver; 3) The regulatory function of tumor induced MDSC on NK T cells in liver and what is the molecular mechanisms. We expect to make some progress on the mechanisms of how tumor induce immune tolerance in some organs such as liver and how tumor induced inhibitory immune cells regulate NK T cells in liver. Our work will provide some basis for the immune therapy targeting the tumor induced immune tolerance.

肿瘤可通过诱导免疫耐受抑制机体多部位的免疫应答，逃避免疫监视。我们的研究表明，给小鼠皮下接种B16黑色素瘤细胞可抑制肝脏内ConA诱导的损伤。进一步的研究表明，随着肿瘤的生长，血液中表达趋化因子受体CXCR2的MDSC比例升高，MDSC趋化能力增强并聚集到肝脏中，通过细胞接触依赖性的机制作用于NK T细胞，抑制其IFN-γ的表达，从而使NK T细胞不能发挥损伤肝细胞的作用。而MDSC本身的抑制功能并没有增强。这是国际上首次证明MDSC对NK T细胞具有抑制作用。此外，我们的一些初步研究结果表明，如果沉默B16细胞中TGF-β1的表达，荷瘤小鼠可被ConA诱导出较高水平的肝损伤，这表明肿瘤细胞产生的TGF-β1可能在肿瘤诱导的免疫耐受中发挥重要作用。那么，肿瘤细胞产生的TGF-β1在肿瘤诱导的免疫耐受中发挥怎样的作用？不同亚群（Ly6G+ Ly6Clow 和Ly6G- Ly6Chigh）的MDSC是否在肿瘤诱导的肝脏免疫耐受中分别发挥怎样的作用？这将是我们需要继续阐述清楚的内容。