Our previous studies revealed that, upon exposure to hypoxia, tumour cells acquire resistance to the cytolytic activity of IL-2-activated lymphocytes. The MHC class I chain-related (MIC) molecules - comprised of MICA and MICB - are ligands for the activating NKG2D receptor on Natural Killer (NK) and CD8+ T cells. MIC-NKG2D interactions lead to the activation of NK and CD8+ T cells and the subsequent lysis of the tumour cells. We also showed that the mechanism of the hypoxia-mediated immune escape involves the shedding of MICA from the tumour cell surface. The objective of the present study was to determine whether the shedding of MICA requires the expression of hypoxia inducible factor-1 (HIF-1), a transcription factor - comprised of a constitutively expressed \#946; subunit and an O2-regulated \#945; subunit - that regulates cellular adaptations to hypoxia. Exposure to hypoxia (0.5% O2 vs. 20% O2) led to the shedding of MICA from the surface of MDA-MB-231 human breast cancer cells as determined by flow cytometry. Knockdown of HIF-1\#945; mRNA using siRNA technology resulted in inhibition of HIF-1\#945; accumulation under hypoxic conditions as determined by Western blot analysis. Parallel studies revealed that knockdown of HIF-1\#945; also blocked the shedding of MICA from the surface of MDA-MB-231 cells exposed to hypoxia. These results indicate that HIF-1 is required for the hypoxia-mediated shedding of MICA and, consequently, that HIF-1 may play an important role in tumour immune escape. Ongoing studies aim to determine the HIF-1 target genes involved in the shedding of MICA.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 251.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO