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DNAM-1/CD155 Interactions Promote Cytokine and NK Cell-Mediated Suppression of Poorly Immunogenic Melanoma Metastases

Christopher J. Chan,^*,,1 Daniel M. Andrews,^*,1 Nicole M. McLaughlin,^* Hideo Yagita, Susan Gilfillan, Marco Colonna, and Mark J. Smyth^*,

^*Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne; Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110

A role for NK cells in therapeutic intervention for hematologic malignancies, such as acute myeloid leukemia and multiple myeloma, and nonhematologic malignancies, such as melanoma, is becoming more apparent. DNAM-1 is an NK cell receptor whose importance in facilitating activation signals received by NK cells in natural and cytokine-driven responses to tumor metastases in vivo is poorly explored. In this study, we used matched tumor lines expressing a variety of relevant ligands, neutralizing monoclonal Abs, and DNAM-1 gene-targeted mice to determine the relative importance of DNAM-1–ligand interactions in controlling tumor metastases. Our results demonstrate that NK cells require DNAM-1 for natural or cytokine (IL-2, IL-12, or IL-21) suppression of tumor metastases or their variants expressing CD70 or CD80. In contrast, DNAM-1 was dispensable when tumor cells were targets of Ab-dependent cellular cytotoxicity or presented ligands for NKG2D. CD155 appeared to be a key ligand recognized by DNAM-1 in NK cell-mediated suppression of metastases, and DNAM-1-mediated suppression coincided with perforin activity. Overall, these data implied a general role for DNAM-1-CD155 interactions in NK cell-mediated killing of tumors, even in the presence of tumor CD70 or CD80 expression, and further defined the optimal efficacy requirements of cytokines that directly activate NK cells.

Address correspondence and reprint requests to Prof. Mark J. Smyth, Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Melbourne, 8006, Victoria, Australia. E-mail address: mark.smyth{at}petermac.org

¹ C.J.C. and D.M.A. contributed equally to this work.

This work was supported by National Health and Medical Research Council of Australia Program Grant 454569 (to M.J.S.), a Senior Principal Research Fellowship (to M.J.S.), a project grant 566602 (to D.M.A.), a Doherty Fellowship (to D.M.A.), and a Ph.D. Scholarship (to C.J.C.) from the Leukemia Foundation of Australia.

Abbreviations used in this paper:

ADCC, Ab-dependent cellular cytotoxicity; anti-asGM1, anti-asialoGM1; cIg, control immunoglobulin; EWS, Ewing sarcoma; NCR, natural cytotoxicity receptor; NP, nitrophenyl; TIGIT, T cell Ig and ITIM domain; WT, wild-type.