title: Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.
abstract: T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their role in tumor progression is poorly understood. Targeted deletion of the hypoxia-responsive transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although vascular endothelial growth factor-A levels and vascularization were unchanged. Tumor-associated macrophages can suppress tumor-infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T-cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T-cell suppression in the tumor microenvironment.
authors.affiliation: Division of Biological Sciences, School of Medicine, University of California at San Diego, CA 92093, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Doedens
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.forename: Debbie
authors.initials: D
authors.lastname: Liao
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015687:Cell Hypoxia / Q000276:immunology; D018920:Coculture Techniques; D018450:Disease Progression; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D007178:Inbreeding; D008213:Lymphocyte Activation; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse