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Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β1¹

Hequan Li^2,*, Yanmei Han^2,, Qiuli Guo, Minggang Zhang and Xuetao Cao^3,*,

^* 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants 30672386, 30572121, and 30721091 from the National Natural Science Foundation of China, Grant 2007CB512403 from the National Key Basic Research Program of China, and Grant 2008ZX10209 from the National Program of Liver Cancer Research.

² H.L. and Y.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Xuetao Cao, Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. E-mail address: caoxt{at}public3.sta.net.cn

⁴ Abbreviations used in this paper: DC, dendritic cell; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; MLN, mesenteric lymph node; MNC, mononuclear cell; VEGF, vascular endothelial growth factor; 7-AAD, 7-aminoactinomycin D; MFI, mean fluorescence intensity.

⁵ The online version of this article contains supplemental material.

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