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.

Impact of IL-2 and IL-2R SNPs on Proliferation and Tumor-killing Activity of Lymphokine-Activated Killer Cells from Healthy Chinese Blood Donors

“…NK cells can selectively recognize and kill cells that express NK-cell-activating receptors and "non-self" tumor cells that have reduced MHC I expression. Resting NK cells circulate through the peripheral blood, while cytokineactivated NK cells can penetrate blood vessels, and migrate into infection sites or tumors (Chan et al, 2010;Lomonaco et al, 2011).…”

Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+ Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche

“…The EO771 and PyMT mammary carcinoma and B16F10 melanoma cell lines were maintained as previously described (9,10) and infected with the pMSCV-Cherry/Luciferase lentiviral vector for sorting by flow cytometry. Conditioned media was generated by filtering serum-free, phenol red-free low glucose Dulbecco's Modified Eagles Medium (Invitrogen) cultured on cells for 10 hours under normoxic (20% O 2 ) or hypoxic conditions (2% O 2 ; ref.…”

“…Flow cytometry was carried out on a single-cell suspension of whole lung tissue (10). Antibody details listed in Supplementary Methods.…”

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

“…19 Indeed, DNAM-1 triggers NK cell killing of freshly isolated ovarian carcinoma and neuroblastoma cells 20,21 and is required for killing and control of melanoma metastases. 22,23 Similarly, mice lacking DNAM-1 exhibit accelerated growth of DNAM-1 ligandexpressing tumors. 24 Thus, DNAM-1 appears to be a key regulator of NK-cell-mediated cancer immunosurveilance.…”