title: Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection.
abstract: Intratumoral hypoxia and hypoxia inducible factor-1α (HIF-1-α)-dependent CD39/CD73 ectoenzymes may govern the accumulation of tumor-protecting extracellular adenosine and signaling through A2A adenosine receptors (A2AR) in tumor microenvironments (TME). Here, we explored the conceptually novel motivation to use supplemental oxygen as a treatment to inhibit the hypoxia/HIF-1α-CD39/CD73-driven accumulation of extracellular adenosine in the TME in order to weaken the tumor protection. We report that hyperoxic breathing (60 % O2) decreased the TME hypoxia, as well as levels of HIF-1α and downstream target proteins of HIF-1α in the TME according to proteomic studies in mice. Importantly, oxygenation also downregulated the expression of adenosine-generating ectoenzymes and significantly lowered levels of tumor-protecting extracellular adenosine in the TME. Using supplemental oxygen as a tool in studies of the TME, we also identified FHL-1 as a potentially useful marker for the conversion of hypoxic into normoxic TME. Hyperoxic breathing resulted in the upregulation of antigen-presenting MHC class I molecules on tumor cells and in the better recognition and increased susceptibility to killing by tumor-reactive cytotoxic T cells. Therapeutic breathing of 60 % oxygen resulted in the significant inhibition of growth of established B16.F10 melanoma tumors and prolonged survival of mice. Taken together, the data presented here provide proof-of principle for the therapeutic potential of systemic oxygenation to convert the hypoxic, adenosine-rich and tumor-protecting TME into a normoxic and extracellular adenosine-poor TME that, in turn, may facilitate tumor regression. We propose to explore the combination of supplemental oxygen with existing immunotherapies of cancer.
  
  
  CONCLUSIONS
  Oxygenation decreases levels of tumor protecting hypoxia. Oxygenation decreases levels of tumor protecting extracellular adenosine. Oxygenation decreases expression of HIF-1alpha dependent tumor-protecting proteins. Oxygenation increases MHC class I expression and enables tumor regression.
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA, s.hatfield@neu.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hatfield
authors.forename: Jorgen
authors.initials: J
authors.lastname: Kjaergaard
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Lukashev
authors.forename: Bryan
authors.initials: B
authors.lastname: Belikoff
authors.forename: Taylor H
authors.initials: TH
authors.lastname: Schreiber
authors.forename: Shalini
authors.initials: S
authors.lastname: Sethumadhavan
authors.forename: Robert
authors.initials: R
authors.lastname: Abbott
authors.forename: Phaethon
authors.initials: P
authors.lastname: Philbrook
authors.forename: Molly
authors.initials: M
authors.lastname: Thayer
authors.forename: Dai
authors.initials: D
authors.lastname: Shujia
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
authors.forename: Akio
authors.initials: A
authors.lastname: Ohta
authors.forename: Eckhard R
authors.initials: ER
authors.lastname: Podack
authors.forename: Barry
authors.initials: B
authors.lastname: Karger
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Michail
authors.initials: M
authors.lastname: Sitkovsky
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000628:therapy*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000150:complications* / Q000378:metabolism / Q000628:therapy*; D010100:Oxygen / Q000627:therapeutic use*; D059016:Tumor Microenvironment
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000241:Adenosine; D010100:Oxygen