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Tumor-Educated CD11b^highIa^low Regulatory Dendritic Cells Suppress T Cell Response through Arginase I¹

Qiuyan Liu^*, Chaoxiong Zhang^*, Anna Sun, Yuanyuan Zheng^*, Li Wang and Xuetao Cao^2,*,

^* National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, People’s Republic of China; and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China

Tumors can induce generation and accumulation of the immunosuppressive cells such as regulatory T cells in the tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell (DC)-based cancer vaccine can initiate antitumor immune response, regulatory DC subsets involved in the tolerance induction attracted much attention recently. Our previous studies demonstrate that the stromal microenvironment of the spleen, lung, and liver can program generation of CD11c^lowCD11b^highIa^low DCs with regulatory function (CD11b^highIa^low regulatory DCs). However, whether and how the tumor microenvironment can program generation of CD11b^highIa^low regulatory DCs remain to be investigated. In this study, we used the freshly isolated tumor cells to mimic tumor microenvironment to coculture DCs and found that the freshly isolated tumor cells could drive DCs to differentiate into regulatory DCs with a CD11c^lowCD11b^highIa^low phenotype and high expression of IL-10, NO, vascular endothelial growth factor, and arginase I. Tumor-educated CD11b^highIa^low regulatory DCs inhibited CD4⁺ T cell proliferation both in vitro and in vivo. 3LL lung cancer-derived TGF-β and PGE₂ were responsible for the generation of regulatory DCs. PGE₂ was the main inducer of arginase I in regulatory DCs. Arginase I played a major role in the suppression of T cell response by regulatory DCs induced by 3LL lung cancer. A natural counterpart of CD11b^highIa^low DCs was identified in tumor tissue, and CD11b^highIa^low DCs sorted from 3LL lung cancer tissue expressed arginase I and inhibited T cell response. Therefore, tumors can educate DCs to differentiate into a regulatory DC subset, which contributes to constitution of the immunosuppressive tumor microenvironment and promotes 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 from the National Natural Science Foundation of China (Grants 30771984, 30672386, and 30721091) and the National Key Research Program of China (Grant 2007CB512403).

² Address correspondence and reprint requests to Dr. Xuetao Cao, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, People’s Republic of China. E-mail address: caoxt{at}public3.sta.net.cn

³ Abbreviations used in this paper: DC, dendritic cell; DCreg, regulatory DC; mDC, mature DC; imDC, immature DC; TIDC, tumor-infiltrating DC; Treg, regulatory T cell; VEGF, vascular endothelial growth factor; MDSC, myeloid-derived suppressor cells; 7-AAD, 7-aminoactinomycin D; 1,4-PBIT, 1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea dihydrobromide; nor-NOHA, N-hydroxy-nor-L-arginine.

⁴ The online version of this article contains supplemental material.

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