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Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine¹

Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Kwanak-Gu, Seoul, Korea

Myeloid-derived suppressor cells (MDSCs), which are known to be accumulated in the blood, spleen, and bone marrow of tumor-bearing mice and cancer patients, were tested as APCs for a cellular vaccine because they have phenotypical similarity with inflammatory monocytes and may be differentiated from the same precursors as monocytes. Although MDSCs have immunosuppressive properties, in vivo transferred MDSCs, which present tumor Ag and NKT cell ligand (-galactosylceramide), significantly prolonged survival time in metastatic tumor-bearing mice in a CD8⁺ cell-, NK cell-, and NKT cell-dependent manner vs a CD4⁺ T cell- and host dendritic cell-independent manner. Major concerns about using MDSCs as APCs in a vaccine are their suppression of CTLs and their induction of Foxp3⁺ regulatory T cells. However, -galactosylceramide-loaded MDSCs did not suppress CD4⁺ and CD8⁺ T cells and allowed for the generation of Ag-specific CTL immunity without increasing the generation of regulatory T cells. Furthermore, stimulation with activated NKT cells induced changes on MDSCs in phenotypical or maturation markers, including CD11b, CD11c, and CD86. Taken together, these findings suggest that NKT cells facilitate the conversion of immunosuppressive MDSCs into immunogenic APCs, eliciting successful antitumor immunity and providing the basis for alternative cell-based vaccines.

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 study was supported by a grant from the National Research and Development Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (0720500-1) and a Korea Science and Engineering Foundation National Research Laboratory Program grant funded by the Ministry of Education, Science and Technology, Republic of Korea (R0A-2008-000-20113-0).

² Address correspondence and reprint requests to Dr. Chang-Yuil Kang, Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Kwanak-Gu, Seoul, Korea. E-mail address: cykang{at}snu.ac.kr

³ Abbreviations used in this paper: DC, dendritic cell; AdHM, adenovirus encoding Her-2/neu encoding extracellular and transmembrane domain; GalCer, -galactosylceramide; DTX, diphtheria toxin; MDSC, myeloid-derived suppressor cell; MOI, multiplicity of infection; NKT, NKT (cell); Treg, regulatory T (cell).