The Requirement for DNAM-1, NKG2D, and NKp46 in the Natural Killer Cell-Mediated Killing of Myeloma Cells

Abstract

Recent evidence suggests a role for natural killer (NK) cells in the control of multiple myeloma. We show that expression of the NK cell receptor DNAM-1 (CD226) is reduced on CD56 dim NK cells from myeloma patients with active disease compared with patients in remission and healthy controls. This suggested that this receptor might play a role in NK-myeloma interactions. The DNAM-1 ligands Nectin-2 (CD112) and the poliovirus receptor (PVR; CD155) were expressed by most patient myeloma samples analyzed. NK killing of patientderived myelomas expressing PVR and/or Nectin-2 was DNAM-1 dependent, revealing a functional role for DNAM-1 in myeloma cell killing. In myeloma cell lines, cell surface expression of PVR was associated with low levels of NKG2D ligands, whereas cells expressing high levels of NKG2D ligands did not express PVR protein or mRNA. Furthermore, NK cellmediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. In contrast, the natural cytotoxicity receptor NKp46 was required for the killing of all myeloma cell lines analyzed. Thus, DNAM-1 is important in the NK cell-mediated killing of myeloma cells expressing the cognate ligands. The importance of NKp46, NKG2D, and DNAM-1 in myeloma killing mirrors the differential expression of NK cell ligands by myeloma cells, reflecting immune selection during myeloma disease progression. [Cancer Res 2007;67(18):8444-9]

DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

“…Conversely, using the anti-CD96 NK92.39 mAb, we have not been able to point a role of CD96 in the lysis of Necl-5-expressing HCC cells by gd T effectors. Similarly, others groups did not succeed in demonstrating a contribution of CD96 to the NK-cell-mediated lysis of ovarian carcinoma or myeloma [27,29]. Our experiments indicate that Necl-5 but not Nectin-2 is involved in the DNAM-1-dependent recognition of tumor cells by gd T cells.…”

NK cells and cancer immunosurveillance

“…Examples are the IgSF member DNAX accessory molecule-1 (DNAM-1)/CD226 and the CTLR NKp80 (Pende et al, 2006;Welte et al, 2006). DNAM-1 binds to adhesion molecules poliovirus receptor (PVR/CD155) and Nectin-2 (CD112) which also are IgSF members and broadly are expressed both by 'healthy' and malignant cells of epithelial and hematopoetic origin (Bottino et al, 2003;Pende et al, 2005;Carlsten et al, 2007;El Sherbiny et al, 2007). Engagement of DNAM-1 by these ligands was shown to substantially contribute to anti-tumour NK cytotoxicity (Pende et al, 2005(Pende et al, , 2006Tahara-Hanaoka et al, 2006;Carlsten et al, 2007;El Sherbiny et al, 2007).…”

Primary Human Tumor Cells Expressing CD155 Impair Tumor Targeting by Down-Regulating DNAM-1 on NK Cells

“…Since this receptor is of fundamental importance for the recognition and killing of several human tumors, including ovarian carcinoma (15)(16)(17)29), we next investigated the mechanism behind the modulation of DNAM-1 receptor expression in the tumor environment.…”

“…These studies provide the first direct evidence for a central role for DNAM-1 in tumor immune surveillance. DNAM-1 is important for NK cell-mediated recognition of several human tumors, including neuroblastoma, myeloma, and Ewing sarcoma (16,17,29,35). We have previously shown that the DNAM-1/CD155 interaction is crucial for the recognition of freshly isolated ovarian carcinoma by allogeneic NK cells (15).…”