title: DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases.
abstract: 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.
authors.affiliation: Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chan
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Nicole M
authors.initials: NM
authors.lastname: McLaughlin
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Susan
authors.initials: S
authors.lastname: Gilfillan
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen; D053282:CD27 Ligand; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000276:immunology*; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D000098862:T Lineage-Specific Activation Antigen 1; D053282:CD27 Ligand; D016207:Cytokines; D008024:Ligands; D011991:Receptors, Virus; C066100:poliovirus receptor