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Tumor Exosomes Inhibit Differentiation of Bone Marrow Dendritic Cells¹

Shaohua Yu^*, Cunren Liu^*, Kaihong Su^*, Jianhua Wang^*, Yuelong Liu^*, Liming Zhang^*, Chuanyu Li^*, Yingzi Cong, Robert Kimberly^*, William E. Grizzle, Carla Falkson and Huang-Ge Zhang^2,*,¶

^* Department of Medicine, Division of Clinical Immunology and Rheumatology, Department of Pathology, Department of Medicine, Division of Gastroenterology and Hepatology, and Department of Medicine, Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294; and ^¶ Birmingham Veterans Administration Medical Center, Birmingham, AL 35233

The production of exosomes by tumor cells has been implicated in tumor-associated immune suppression. In this study, we show that, in mice, exosomes produced by TS/A murine mammary tumor cells target CD11b⁺ myeloid precursors in the bone marrow (BM) in vivo, and that this is associated with an accumulation of myeloid precursors in the spleen. Moreover, we demonstrate that TS/A exosomes block the differentiation of murine myeloid precursor cells into dendritic cells (DC) in vitro. Addition of tumor exosomes at day 0 led to a significant block of differentiation into DC, whereas addition at later time points was less effective. Similarly, exosomes produced by human breast tumor cells inhibited the differentiation of human monocytes in vitro. The levels of IL-6 and phosphorylated Stat3 were elevated 12 h after the tumor exosome stimulation of murine myeloid precursors, and tumor exosomes were less effective in inhibiting differentiation of BM cells isolated from IL-6 knockout mice. Addition of a rIL-6 to the IL-6 knockout BM cell culture restored the tumor exosome-mediated inhibition of DC differentiation. These data suggest that tumor exosome-mediated induction of IL-6 plays a role in blocking BM DC differentiation.

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 in part by grants from the National Institutes of Health (P30 AR48311, R01 CA116092, and R01 CA107181) and by Birmingham Veterans Administration Medical Center Merit Review Grants (to H.-G.Z.).

² Address correspondence and reprint requests to Dr. Huang-Ge Zhang, University of Alabama at Birmingham, 1825 University Boulevard SIRB 306 Birmingham, AL 35294. E-mail address: Huang-Ge.Zhang{at}ccc.uab.edu

³ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; KO, knockout; E-control, exosome control; WT, wild type; PI, propidium iodide; MHCII, MHC class II.

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