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Journal of Molecular Medicine

, Volume 92, Issue 12, pp 1283–1292 | Cite as

Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection

  • Stephen M. Hatfield
  • Jorgen Kjaergaard
  • Dmitriy Lukashev
  • Bryan Belikoff
  • Taylor H. Schreiber
  • Shalini Sethumadhavan
  • Robert Abbott
  • Phaethon Philbrook
  • Molly Thayer
  • Dai Shujia
  • Scott Rodig
  • Jeffrey L. Kutok
  • Jin Ren
  • Akio Ohta
  • Eckhard R. Podack
  • Barry Karger
  • Edwin K. Jackson
  • Michail Sitkovsky
Original Article

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.

Key messages

  • 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.

Keywords

Hypoxia HIF-1α Adenosine CD73 Cancer Immunology 

Notes

Acknowledgments

This work was supported by the funding from Northeastern University and NIH grants (PI: M.S.) R01 CA-111985; R01 GM-097320; R01 CA-112561; R21 AT 002788. We thank Dr. Richard Marsh, an expert in the field of energetics, kinematics, and kinetics for assistance with monitoring gas compositions in hyperoxia units.

Conflict of interest

The authors declare they have no competing interests as defined by Molecular Medicine or other interests that might be perceived to influence the results and discussion reported in this paper.

Supplementary material

109_2014_1189_MOESM1_ESM.pdf (2.3 mb)
ESM 1 (PDF 2,396 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Stephen M. Hatfield
    • 1
  • Jorgen Kjaergaard
    • 1
  • Dmitriy Lukashev
    • 1
  • Bryan Belikoff
    • 1
  • Taylor H. Schreiber
    • 3
  • Shalini Sethumadhavan
    • 1
  • Robert Abbott
    • 1
  • Phaethon Philbrook
    • 1
  • Molly Thayer
    • 1
  • Dai Shujia
    • 5
  • Scott Rodig
    • 4
  • Jeffrey L. Kutok
    • 4
  • Jin Ren
    • 6
  • Akio Ohta
    • 1
  • Eckhard R. Podack
    • 3
  • Barry Karger
    • 5
  • Edwin K. Jackson
    • 6
  • Michail Sitkovsky
    • 1
    • 2
  1. 1.New England Inflammation and Tissue Protection InstituteNortheastern UniversityBostonUSA
  2. 2.Cancer Vaccine Center, Dana Farber Cancer InstituteHarvard Institutes of MedicineBostonUSA
  3. 3.Department of Microbiology and Immunology, Miller School of MedicineUniversity of MiamiMiamiUSA
  4. 4.Department of Pathology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  5. 5.Barnett Institute and Department of Chemistry and Chemical BiologyNortheastern UniversityBostonUSA
  6. 6.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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