title: A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.
abstract: 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-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α 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-1α 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.
authors: Authors' Affiliations: Departments of Biomedical and Molecular Sciences and Urology, Queen's University, Kingston, Ontario, Canada.
authors: Ivraym B
authors: IB
authors: Barsoum
authors: Chelsea A
authors: CA
authors: Smallwood
authors: D Robert
authors: DR
authors: Siemens
authors: Charles H
authors: CH
authors: Graham
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005996:Nitroglycerin / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D061026:Programmed Cell Death 1 Receptor; D005996:Nitroglycerin