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

Abstract

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 NOmediated 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 Mg/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]

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8+ T‐cell recognition of stressed cells

“…In earlier reports, exposure to hypoxia alone increased tumor cell shedding of MHC class I chain-related (MIC) molecules, which are the ligand of NKG2D receptor, thereby conferring resistance to the immune surveillance [34]. Meanwhile, exposure to glucose deprivation alone affected neither the synthesis of MHC I mRNA nor the amount of intracellular MHC I protein, but decreased the surface amount of H-2K b presenting the model antigenic peptide, SIINFEKL derived from OVA, on the stressed cells [35].…”

“…In earlier reports, exposure to hypoxia alone increased tumor cell shedding of MHC class I chain-related (MIC) molecules, which are the ligand of NKG2D receptor, thereby conferring resistance to the immune surveillance [34]. Immunol.…”

From tumor cell metabolism to tumor immune escape

“…MICs (MICA and MICB) are induced upon cell stress in normal cells; however, they are constitutively expressed in many tumors. MICs are recognized by NK cells, NKT cells, and most of the subtypes of T cells (Siemens et al, 2008). Surface expression of MICs is under the control of extracellular as well as intracellular events.…”

L’hypoxie tumorale

“…[21]. Les TAM sont localisés préférentiel-lement au niveau des zones tumorales hypoxiques où, MICA à la surface cellulaire [18,19]. MICA étant un ligand du récepteur activateur NKG2D (natural killer group 2D) présent à la surface des cellules NK et des lymphocytes T, cette diminution aboutit à l'échappe-ment des cellules tumorales à la lyse par les NK et CTL [18,19].…”

“…Les TAM sont localisés préférentiel-lement au niveau des zones tumorales hypoxiques où, MICA à la surface cellulaire [18,19]. MICA étant un ligand du récepteur activateur NKG2D (natural killer group 2D) présent à la surface des cellules NK et des lymphocytes T, cette diminution aboutit à l'échappe-ment des cellules tumorales à la lyse par les NK et CTL [18,19]. Dans le contexte des mutations VHL observées dans les carcinomes du rein à cellules claires, l'inhibition de HIF-1 dans des cellules tumorales stabilisant HIF-1 et HIF-2 est associée à une résistance aux cellules NK par une diminution de l'expression des molécules du système HLA de classe I [20].…”