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

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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.

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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.

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Authors and Affiliations

  1. New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA

    Stephen M. Hatfield, Jorgen Kjaergaard, Dmitriy Lukashev, Bryan Belikoff, Shalini Sethumadhavan, Robert Abbott, Phaethon Philbrook, Molly Thayer, Akio Ohta & Michail Sitkovsky

  2. Cancer Vaccine Center, Dana Farber Cancer Institute, Harvard Institutes of Medicine, Boston, MA, 02115, USA

    Michail Sitkovsky

  3. Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

    Taylor H. Schreiber & Eckhard R. Podack

  4. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Scott Rodig & Jeffrey L. Kutok

  5. Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA

    Dai Shujia & Barry Karger

  6. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Jin Ren & Edwin K. Jackson

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  1. Stephen M. Hatfield
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Correspondence to Stephen M. Hatfield or Michail Sitkovsky.

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Hatfield, S.M., Kjaergaard, J., Lukashev, D. et al. Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection. J Mol Med 92, 1283–1292 (2014). https://doi.org/10.1007/s00109-014-1189-3

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  • DOI: https://doi.org/10.1007/s00109-014-1189-3

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