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DAP10 Deficiency Breaks the Immune Tolerance against Transplantable Syngeneic Melanoma¹

Cellular Immunology Laboratory, Department of Discovery Research, Schering-Plough Biopharma, Palo Alto, CA 94304

DAP10, an activating adaptor protein, associates with the NKG2D protein to form a multisubunit receptor complex that is expressed in lymphoid and myeloid cells. The ligands for NKG2D-DAP10 receptor are expressed in both normal and tumor cells, suggesting distinct roles for this receptor in autoimmunity and cancer. In this study, we report that constitutive DAP10 activating signaling is part of regulatory mechanisms that control immunity against tumors. Mice lacking DAP10 (DAP10KO), showed enhanced immunity against melanoma malignancies due to hyperactive functioning of NK1.1⁺CD3⁺ NKT cells. DAP10 deficiency resulted in substantially increased NKT cell functions, including cytokine production and cytotoxicity, leading to efficient killing of melanoma tumors. Moreover, the antitumor phenotype of DAP10KO mice correlated with impaired activation status of CD4⁺CD25⁺ T regulatory cells (Tregs). Upon activation, DAP10KO Tregs maintained higher levels of IL-2 and produced significantly lower amounts of IL-10 and IFN- cytokines when compared with wild-type Tregs. Our data suggest that DAP10 signaling is involved in adjusting the activation threshold and generation of NKT cells and Tregs to avoid autoreactivity, but also modulates antitumor mechanisms.

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 Schering Plough.

² Address correspondence and reprint requests to Dr. Nevila Hyka-Nouspikel at the current address: Institute for Cancer Studies, Medical School, University of Sheffield, Beech Hill Road, S10 2RX Sheffield, U.K. E-mail address: Nevila.Nouspikel{at}sheffield.ac.uk

³ Abbreviations used in this paper: WT, wild type; Treg, T regulatory cell.