DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases.
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.
Chan
Christopher J
CJ
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Andrews
Daniel M
DM
McLaughlin
Nicole M
NM
Yagita
Hideo
H
Gilfillan
Susan
S
Colonna
Marco
M
Smyth
Mark J
MJ
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
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