In the current research we describe a novel mechanism by which hypoxia contributes to tumour cell escape from lysis mediated by cytotoxic T lymphocytes (CTLs). Specifically, we show that when exposed to hypoxia for 24 h, human DU145 prostate and MDA-MB-231 breast cancer cells, as well as mouse B16-OVA melanoma cells, increased their expression of the immune inhibitory ligand B7-H1 at both the mRNA and protein levels in a manner dependent on hypoxia-inducible factor-1α (HIF-1α). Moreover, our findings revealed that the hypoxia-induced up-regulation of B7-H1 expression in tumour cells resulted in increased tumour cell resistance to lysis mediated by primed CTLs. We previously demonstrated that activation of nitric oxide (NO) signalling blocks HIF-1α accumulation in tumour cells exposed to hypoxia. Here we show that the NO mimetic glyceryl trinitrate (GTN; 10 nM) prevented the hypoxia-induced up-regulation of tumour cell B7-H1 expression as well as the increased resistance to CTL-mediated lysis. Furthermore, co-culture studies revealed that the increased expression of B7-H1 following exposure of tumour cells to hypoxia led to the apoptotic death of CTLs as well as Jurkat leukemia cells in a manner that could be prevented by blocking B7-H1, programmed cell death-1 receptor (B7-H1 receptor expressed by T cells) or by incubation with low concentrations of GTN. These results indicate that a potential immunotherapy of cancer could involve interference with B7-H1 function in hypoxic tumour cells via administration of NO mimetics.

Citation Format: Ivraym B. Barsoum, Chelsea A. Smallwood, D. Robert Siemens, Charles H. Graham. Hypoxia induces tumor cell escape from T cell-mediated immunity via up-regulation of B7-H1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 447. doi:10.1158/1538-7445.AM2013-447