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Hypoxia Increases Tumor Cell Shedding of MHC Class I Chain-Related Molecule: Role of Nitric Oxide

¹ Department of Anatomy and Cell Biology, ² Department of Urology, and ³ Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada and ⁴ Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

Requests for reprints: Charles H. Graham, Department of Anatomy and Cell Biology, Botterell Hall 9th Floor, Queen's University, Kingston, Ontario, Canada K7L 3N6. Phone: 613-533-2600; Fax: 613-533-2566; E-mail: grahamc{at}queensu.ca.

Key Words: cancer • immune surveillance • hypoxia • nitric oxide • MIC

The MHC class I chain-related (MIC) molecules play important roles in tumor immune surveillance through their interaction with the NKG2D receptor on natural killer and cytotoxic T cells. Thus, shedding of the MIC molecules from the tumor cell membrane represents a potential mechanism of escape from NKG2D-mediated immune surveillance. Tumor hypoxia is associated with a poor clinical outcome for cancer patients. We show that hypoxia contributes to tumor cell shedding of MIC through a mechanism involving impaired nitric oxide (NO) signaling. Whereas hypoxia increased MIC shedding in human prostate cancer cells, activation of NO signaling inhibited hypoxia-mediated MIC shedding. Similar to incubation in hypoxia, pharmacologic inhibition of endogenous NO signaling increased MIC shedding. Parallel studies showed hypoxia-mediated tumor cell resistance to lysis by interleukin 2–activated peripheral blood lymphocytes (PBL) and NO-mediated attenuation of this resistance to lysis. Inhibition of NO production also led to resistance to PBL-mediated lysis. Interference of MIC-NKG2D interaction with a blocking anti-MIC antibody abrogated the effect of hypoxia and NO signaling on tumor cell sensitivity to PBL-mediated lysis. Finally, continuous transdermal delivery of the NO mimetic glyceryl trinitrate (7.3 µg/h) attenuated the growth of xenografted MIC-expressing human prostate tumors. These findings suggest that the hypoxic tumor microenvironment contributes to resistance to immune surveillance and that activation of NO signaling is of potential use in cancer immunotherapy. [Cancer Res 2008;68(12):4746–53]