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DNAX Accessory Molecule-1 Mediated Recognition of Freshly Isolated Ovarian Carcinoma by Resting Natural Killer Cells

¹ Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge; ² Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet; ³ Department of Obstetrics and Gynecology, Karolinska University Hospital Solna, Stockholm, Sweden and ⁴ Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Karl-Johan Malmberg, Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden. Phone: 46-8-58589688; Fax: 46-8-7466280; E-mail: kalle.malmberg{at}ki.se.

Although natural killer (NK) cells are well known for their ability to kill tumors, few studies have addressed the interactions between resting (nonactivated) NK cells and freshly isolated human tumors. Here, we show that human leukocyte antigen class I^low tumor cells isolated directly from patients with advanced ovarian carcinoma trigger degranulation by resting allogeneic NK cells. This was paralleled by induction of granzyme B and caspase-6 activities in the tumor cells and significant tumor cell lysis. Ovarian carcinoma cells displayed ubiquitous expression of the DNAX accessory molecule-1 (DNAM-1) ligand PVR and sparse/heterogeneous expression of the NKG2D ligands MICA/MICB and ULBP1, ULBP2, and ULBP3. In line with the NK receptor ligand expression profiles, antibody-mediated blockade of activating receptor pathways revealed a dominant role for DNAM-1 and a complementary contribution of NKG2D signaling in tumor cell recognition. These results show that resting NK cells are capable of directly recognizing freshly isolated human tumor cells and identify ovarian carcinoma as a potential target for adoptive NK cell–based immunotherapy. [Cancer Res 2007;67(3):1317–25]

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