A Mechanism of Hypoxia-Mediated Escape from Adaptive Immunity in Cancer Cells

作者：Barsoum, Ivraym B.; Smallwood, Chelsea A.; Siemens, D. Robert; Graham, Charles H.^*

来源：Cancer Research, 2014, 74(3): 665-674.

DOI：10.1158/0008-5472.CAN-13-0992

• NITRIC-OXIDE
• B7-H1 EXPRESSION
• TUMOR
• IMMUNOTHERAPY
• MOLECULES
• RESPONSES

Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha). In vivo studies also demonstrated cellular colocalization of HIF-1 alpha and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1 alpha accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.

• 出版日期2014-2-1