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* Center for Surgery Research, Department of Immunology, Cleveland Clinic, Cleveland, OH 44195;
Pediatric Department, General Hospital of Tianjin Medical University, Tianjin, China; and
Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
Suppression of tumor-specific T cell sensitization is a predominant mechanism of tumor escape. To identify tumor-induced suppressor cells, we transferred spleen cells from mice bearing progressive MCA205 sarcoma into sublethally irradiated mice. These mice were then inoculated subdermally with tumor cells to stimulate T cell response in the tumor-draining lymph-node (TDLN). Tumor progression induced splenomegaly with a dramatic increase (22.1%) in CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) compared with 2.6% of that in normal mice. Analyses of therapeutic effects by the adoptive immunotherapy revealed that the transfer of spleen cells from tumor-bearing mice severely inhibited the generation of tumor-immune T cells in the TDLN. We further identified MDSC to be the dominant suppressor cells. However, cells of identical phenotype from normal spleens lacked the suppressive effects. The suppression was independent of CD4+CD25+ regulatory T cells. Intracellular IFN-
staining revealed that the transfer of MDSC resulted in a decrease in numbers of tumor-specific CD4+ and CD8+ T cells. Transfer of MDSC from MCA207 tumor-bearing mice also suppressed the MCA205 immune response indicating a lack of immunologic specificity. Further analyses demonstrated that MDSC inhibited T cell activation that was triggered either by anti-CD3 mAb or by tumor cells. However, MDSC did not suppress the function of immune T cells in vivo at the effector phase. Our data provide the first evidence that the systemic transfer of MDSC inhibited and interfered with the sensitization of tumor-specific T cell responses in the TDLN.
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 These studies were supported by a grant from the National Cancer Institute (RO1 CA103946).
2 Address correspondence and reprint requests to Dr. Suyu Shu, Center for Surgery Research NE62, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: suyushu{at}aol.com
3 Abbreviations used in this paper: Treg, regulatory T cell; MDSC, myeloid-derived suppressor cell; TDLN, tumor-draining lymph-node; s.d., subdermally; Foxp3, forkhead box P3.
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