J.Immunology：解析肿瘤免疫逃避机制

浙江大学医学院免疫学系特聘教授，浙江大学医学院免疫学研究所所长，第二军医大医学院教授曹雪涛院士继08年岁末在《血液》（Blood）发表免疫学成果后，2009年开年又于《免疫学杂志》（The Journal of Immunology）发表文章。
自然杀伤细胞（Nature Killer Cell，NK）是机体重要的免疫细胞，尤其在抗击肿瘤的过程中发挥重要的作用。来自骨髓的抑制性细胞（myeloid-derived suppressor cells，MDSC），一类表达CD11b+Gr-1+的髓样细胞，在肿瘤发生的过程中出现异常的过度表达现象，大量的MDSC细胞能抑制T细胞和树突状细胞发挥免疫活性，导致肿瘤细胞可逃避免疫系统。然而，MDSC细胞对NK细胞天然免疫功能的调节作用还有待深入调查研究。
在本研究中，曹雪涛院士研究小组对该问题进行研究，将肿瘤移植到动物模型中，结果发现，MDSC细胞对肝脏和脾脏中的NK细胞具有强大的抑制作用，使得NK细胞无法发挥天然免疫功能，这些结果表明，肿瘤损伤肝脏中的NK细胞是一个普遍的现象。研究小组接下来研究肝癌移植小鼠模型，探索肝脏NK细胞如何受到损坏。
结果发现，肝脏和脾脏中的MDSC细胞与NK细胞的关系，当MDSC细胞增多则NK细胞的免疫功能下降。MDSC能抑制NK细胞表达细胞毒性标志NKG2D以及IFN-γ。此外，MDSC细胞抑制Nk细胞的能力由细胞膜表面的TGF-β1来控制。研究还发现，当MDSC细胞减少时，NK细胞的功能可逐步得到恢复，但是调节性T细胞对NK细胞的作用却不因调节性T细胞的减少而得到恢复。
这些研究结果表明，MDSC细胞通过TGF-β1诱导NK细胞失去功能。这也说明，MDSC细胞而不是调节性T细胞是NK细胞的负功能调节因子。研究结果为肿瘤逃避免疫系统提供了新的视野。
该研究项目受到国家自然科学基金资助。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Immunology, 2009, 182: 240-249.
Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β11
Hequan Li2,*, Yanmei Han2,, Qiuli Guo, Minggang Zhang and Xuetao Cao3,*,
* Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, and Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, Peoples Republic of China
NK cells, the important effector of innate immunity, play critical roles in the antitumor immunity. Myeloid-derived suppressor cells (MDSC), a population of CD11b+Gr-1+ myeloid cells expanded dramatically during tumor progression, can inhibit T cells and dendritic cells, contributing to tumor immune escaper. However, regulation of NK cell innate function by MDSC in tumor-bearing host needs to be investigated. In this study, we found that the function of NK cells from liver and spleen was impaired significantly in all tumor-bearing models, indicating the impairment of hepatic NK cell function by tumor is a universal phenomenon. Then we prepared the orthotopic liver cancer-bearing mice as tumor model to investigate how hepatic NK cells are impaired. We show that down-regulation of NK cell function is inversely correlated with the marked increase of MDSC in liver and spleen. MDSC inhibit cytotoxicity, NKG2D expression, and IFN- production of NK cells both in vitro and in vivo. After incubation with MDSC, NK cells could not be activated to produce IFN-. Furthermore, membrane-bound TGF-β1 on MDSC is responsible for MDSC-mediated suppression of NK cells. The impaired function of hepatic NK cells in orthotopic liver cancer-bearing mice could be restored by depletion of MDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC can induce anergy of NK cells via membrane-bound TGF-β1. MDSC, but not regulatory T cells, are main negative regulator of hepatic NK cell function in tumor-bearing host. Our study provides new mechanistic explanations for tumor immune escape.