THE EFFECT OF HYPOXIA INDUCIBLE FACTOR-1 ON THE EXPRESSION OF THE COINHIBITORY LIGANDS B7-H3 AND B7-H1 IN CANCER: RELEVANCE TO CANCER IMMUNE ESCAPE
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The interactions between tumour cells and cells of the immune system are important in the natural evolution of cancer, and the acquired immune system plays an integral role in cancer immune escape. B7-H3 and B7-H1 ligands provide coinhibitory signals to T cells resulting in T cell anergy or apoptosis and their expression has been shown to increase in cancer cells. Tumour hypoxia (oxygen concentration below physiological level) is a major contributor to the spread of cancer and resistance to radiation and chemotherapy. We proposed that hypoxia results in the upregulation of the B7 molecules B7-H3 and B7-H1. Furthermore, studies in our laboratory have shown that acquisition of malignant properties in tumour cells exposed to hypoxia can be inhibited by low concentrations of nitric oxide mimetic agents such as glyceryl trinitrate (GTN). Using cultured breast and prostate cancer cells, we investigated whether the hypoxia-inducible factor HIF-1α, would mediate an upregulation of these ligands. Using a mouse model, we investigated the effect of GTN on tumour growth in vivo. For the in vitro studies, we exposed MDA-MB-231 and MCF-7 breast cancer cells and DU-145 prostate cancer cells to standard culture conditions, hypoxic conditions, or 100 μM CoCl2 (stabilizes HIF-1α) for 24 hours. Our findings indicate that B7-H3 mRNA was upregulated in hypoxia (P = 0.0101). Contrary to our hypothesis, B7-H3 protein was not upregulated in hypoxia. Interestingly, increased B7-H1 protein expression correlated with increased HIF-1α expression (r2=0.48, P<0.0001), and HIF-1α bound to the hypoxia response element (HRE) of B7-H1. These results indicate a role for HIF-1α in the upregulation of B7-H1 levels in MDA-MB-231 cells. While in vitro studies indicated no effect of GTN, a study using female BALB/c mice injected with 4T1 mammary carcinoma cells resulted in a decrease in tumour volume in the GTN treated mice. Together, these results indicate a novel role for HIF-1α in the up-regulation of B7-H1 on cancer cells, thus potentially contributing to immune escape of cancer cells and additionally, a role for GTN as a possible breast cancer therapy.