The major histocompatibility complex class I chain-related (MIC) molecules play important roles in tumor immune surveillance through their interaction with the NKG2D receptor on NK and cytotoxic T cells. Thus, shedding of MIC 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 and with malignant tumor cell phenotypes. We show that hypoxia contributes to tumor cell shedding of MIC through a mechanism involving impaired nitric oxide (NO) signaling. While hypoxia increased MIC shedding in human prostate cancer cells, activation of NO signaling inhibited hypoxia-mediated MIC shedding. Similar to incubation in hypoxia, pharmacological inhibition of endogenous NO signaling increased MIC shedding. Parallel studies showed tumor cell resistance to lysis by IL-2-activated peripheral blood lymphocytes (PBLs) 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/hour) attenuated the growth of MIC-expressing human prostate tumors xenografted in nude mice. These findings suggest that the hypoxic tumor microenvironment contributes to impaired immune surveillance and that activation of NO signaling is of potential use in cancer immunotherapy. (Supported by the Canadian Institutes of Health Research, the United States Army Medical Research and Materiel Command, the Prostate Cancer Research Foundation of Canada, and the ‘Ride-for-Dad’ Campaign).
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA