title: Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes.
abstract: OBJECTIVE
  Adaptation to host immune surveillance is now recognized as a hallmark of cancer onset and progression, and represents an early, indispensable event in cancer evolution. This process of evolution is first instigated by an immune selection pressure imposed by natural host surveillance mechanisms and may then be propagated by vaccination or other types of immunotherapy.
  
  
  METHODS
  We developed a system to simulate cancer evolution in a live host and to dissect the mechanisms responsible for adaptation to immune selection. Here, we show that the oxygen-sensitive α subunit of hypoxia-inducible factor 1 (HIF-1α) plays a central role in cancer immune adaptation under conditions of normal oxygen tension.
  
  
  RESULTS
  We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice. The effects of HIF-1α on immune adaptation were mediated through VEGFA-dependent activation of the AKT and ERK signaling pathways, which induced an antiapoptotic gene expression network in tumor cells.
  
  
  CONCLUSIONS
  Our study therefore establishes a link between immune selection, overexpression of HIF-1α, and cancer immune adaptation under normoxia, providing new opportunities for molecular intervention in patients with cancer.
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea. Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Division of Brain Korea 21 Project for Biomedical Science, Department of Dermatology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Bae
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea. Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sang-kyu
authors.initials: SK
authors.lastname: Ye
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Chih-Ping
authors.initials: CP
authors.lastname: Mao
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland. wutc@jhmi.edu twkim0421@korea.ac.kr.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea. Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea. wutc@jhmi.edu twkim0421@korea.ac.kr.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D010100:Oxygen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D010100:Oxygen