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Primary Human Tumor Cells Expressing CD155 Impair Tumor Targeting by Down-Regulating DNAM-1 on NK Cells¹

Mattias Carlsten,^2* Håkan Norell, Yenan T. Bryceson,^* Isabel Poschke, Kjell Schedvins, Hans-Gustaf Ljunggren,^* Rolf Kiessling, and Karl-Johan Malmberg^2*

^*Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden

The activating NK cell receptor DNAX accessory molecule-1 (DNAM-1) contributes to tumor immune surveillance and plays a crucial role in NK cell-mediated recognition of several types of human tumors, including ovarian carcinoma. Here, we have analyzed the receptor repertoire and functional integrity of NK cells in peritoneal effusions from patients with ovarian carcinoma. Relative to autologous peripheral blood NK cells, tumor-associated NK cells expressed reduced levels of the DNAM-1, 2B4, and CD16 receptors and were hyporesponsive to HLA class I-deficient K562 cells and to coactivation via DNAM-1 and 2B4. Moreover, tumor-associated NK cells were also refractory to CD16 receptor stimulation, resulting in diminished Ab-dependent cellular cytotoxicity against autologous tumor cells. Coincubation of NK cells with ovarian carcinoma cells expressing the DNAM-1 ligand CD155 led to reduction of DNAM-1 expression. Therefore, NK cell-mediated rejection of ovarian carcinoma may be limited by perturbed DNAM-1 expression on tumor-associated NK cells induced by chronic ligand exposure. Thus, these data support the notion that tumor-induced alterations of activating NK cell receptor expression may hamper immune surveillance and promote tumor progression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Swedish Foundation for Strategic Research, the Swedish Society for Medical Research, the Swedish Research Council, the Swedish Cancer Society, the Swedish Children’s Cancer Foundation, the Cancer Society of Stockholm, the Åke Wiberg Foundation, the Royal Swedish Academy of Science, the Tobias Foundation, the Mary Beve Foundation, the David and Astrid Hagelens Foundation, the Abney Foundation, and "ALF-Project" grants from the Stockholm City Council.

² Address correspondence and reprint requests to Dr. Karl-Johan Malmberg and Dr. Mattias Carlsten, Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, S-14186 Stockholm, Sweden. E-mail addresses: kalle.malmberg{at}ki.se and mattias.carlsten{at}ki.se

³ Abbreviations used in this paper: KIR, killer Ig-like receptor; DNAM-1, DNAX accessory molecule-1; ADCC, Ab-dependent cellular cytotoxicity; TANK, tumor-associated NK.

⁴ The online version of this article contains supplemental material.