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Myeloid-Derived Suppressor Cells Down-Regulate L-Selectin Expression on CD4⁺ and CD8⁺ T Cells¹

Erica M. Hanson^*, Virginia K. Clements^*, Pratima Sinha^*, Dan Ilkovitch and Suzanne Ostrand-Rosenberg^2,*

^* Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250; and Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136

Effective cell-mediated antitumor immunity requires the activation of tumor-reactive T cells and the trafficking of activated T cells to tumor sites. These processes involve the extravasation of lymphocytes from the blood and lymphatics, and their homing to lymph nodes and tumors. L-selectin (CD62L) is an important molecule in these processes. It directs naive lymphocytes to peripheral lymph nodes where they become activated and it traffics naive lymphocytes to inflammatory environments, such as tumors. Individuals with advanced cancer are immune suppressed due to myeloid-derived suppressor cells (MDSC), a population of immature myeloid cells that accumulate to high levels in response to tumor-secreted and proinflammatory factors. We now demonstrate that the reduction in T cell levels of L-selectin that is commonly seen in individuals with cancer inversely correlates with MDSC levels. Three lines of evidence demonstrate that MDSC directly down-regulate L-selectin on naive T cells: 1) naive T cells cocultured with tumor-induced MDSC have reduced L-selectin; 2) T cells in tumor-free aged mice with elevated levels of MDSC have reduced L-selectin, and 3) peritoneal exudate T cells of tumor-free mice treated with plasminogen activator urokinase to elevate MDSC have reduced levels of L-selectin. MDSC are likely to down-regulate L-selectin through their plasma membrane expression of ADAM17 (a disintegrin and metalloproteinase domain 17), an enzyme that cleaves the ectodomain of L-selectin. Therefore, MDSC down-regulate L-selectin levels on naive T cells, decreasing their ability to home to sites where they would be activated. This is another mechanism by which MDSC inhibit antitumor immunity.

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 National Institutes of Health Grants R01CA115880 and R01CA84232 and Susan G. Komen For the Cure Grant BCTR0503885. E.M.H. was supported by National Research Service Award 5F32CA119768-03.

² Address correspondence and reprint requests to Dr. Suzanne Ostrand-Rosenberg, Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250. E-mail address: srosenbe{at}umbc.edu

³ Abbreviations used in this paper: TDLN, tumor-draining lymph node; ADAM17, a disintegrin and metalloproteinase 17 (also known as TACE); HA, hemagglutinin; LN, lymph node; MCF, mean channel fluorescence; MDSC, myeloid-derived suppressor cell; NDLN, nondraining lymph node; TC, tri-color; uPA, urokinase plasminogen activator.