Here we describe a novel mechanism by which hypoxia contributes to tumour cell escape from cytotoxic T lymphocyte (CTL)-mediated lysis. When exposed to hypoxia for 24 h, human DU145 prostate and MDA-MB-231 breast cancer cells, as well as mouse B16-OVA melanoma and 4T1 mammary carcinoma cells increased their expression of the immune inhibitory molecule programmed death ligand-1 (PD-L1, also known as B7-H1) in a manner dependent on hypoxia-inducible factor-1α (HIF-1α). Furthermore, in vivo studies demonstrated cellular co-localization of HIF-1α and PD-L1 in 4T1 tumours. The hypoxia-induced expression of PD-L1 in cultured tumour cells resulted in increased resistance to CTL-mediated lysis. Activation of nitric oxide (NO) signalling, using low concentrations of NO mimetics, is known to block HIF-1α accumulation in hypoxic tumour cells. Here we show that low concentrations of the NO mimetic glyceryl trinitrate (GTN; 10 nM) prevented the hypoxia-induced PD-L1 expression as well as the increased resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN (1.8 µg/h) attenuated 4T1 tumour growth in mice. Finally, higher expression of PD-L1 following in vitro exposure of tumour cells to hypoxia led to increased apoptosis of co-cultured CTLs and Jurkat T cell leukemia cells. This hypoxia-induced increase in CTL apoptosis was prevented by blocking PD-L1, PD-1 (PD-L1 receptor on T cells), or by incubation with low concentrations of GTN. These findings point to a role for hypoxia/HIF-1 in attenuating anti-tumour adaptive immunity, and reveal a potential immunotherapy of cancer involving inhibition of PD-L1 expression in hypoxic tumour cells via administration of NO mimetics.

This content is only available via PDF.

Article PDF first page preview

Article PDF first page preview