Immunological mechanisms of the antitumor effects of supplemental oxygenation

Stephen M. Hatfield, Jorgen Kjaergaard, Dmitriy Lukashev, Taylor H. Schreiber, Bryan Belikoff, Robert Abbott, Shalini Sethumadhavan, Phaethon Philbrook, Kami Ko, Ryan Cannici, Molly Thayer, Scott Rodig, Jeffrey L. Kutok, Edwin K. Jackson, Barry Karger, Eckhard R. Podack, Akio Ohta, Michail V. Sitkovsky

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell-and natural killer cell-dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer.

Original languageEnglish (US)
JournalScience Translational Medicine
Volume7
Issue number277
DOIs
StatePublished - Mar 4 2015
Externally publishedYes

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Tumor Microenvironment
Immunosuppression
Hyperoxia
T-Lymphocytes
Adenosine
Immunotherapy
Neoplasms
Adenosine A2A Receptors
Transforming Growth Factors
Regulatory T-Lymphocytes
Immunosuppressive Agents
varespladib methyl
Natural Killer Cells
Breast Neoplasms
Cytokines
Oxygen
Neoplasm Metastasis
Lung
Hypoxia
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hatfield, S. M., Kjaergaard, J., Lukashev, D., Schreiber, T. H., Belikoff, B., Abbott, R., ... Sitkovsky, M. V. (2015). Immunological mechanisms of the antitumor effects of supplemental oxygenation. Science Translational Medicine, 7(277). https://doi.org/10.1126/scitranslmed.aaa1260

Immunological mechanisms of the antitumor effects of supplemental oxygenation. / Hatfield, Stephen M.; Kjaergaard, Jorgen; Lukashev, Dmitriy; Schreiber, Taylor H.; Belikoff, Bryan; Abbott, Robert; Sethumadhavan, Shalini; Philbrook, Phaethon; Ko, Kami; Cannici, Ryan; Thayer, Molly; Rodig, Scott; Kutok, Jeffrey L.; Jackson, Edwin K.; Karger, Barry; Podack, Eckhard R.; Ohta, Akio; Sitkovsky, Michail V.

In: Science Translational Medicine, Vol. 7, No. 277, 04.03.2015.

Research output: Contribution to journalArticle

Hatfield, SM, Kjaergaard, J, Lukashev, D, Schreiber, TH, Belikoff, B, Abbott, R, Sethumadhavan, S, Philbrook, P, Ko, K, Cannici, R, Thayer, M, Rodig, S, Kutok, JL, Jackson, EK, Karger, B, Podack, ER, Ohta, A & Sitkovsky, MV 2015, 'Immunological mechanisms of the antitumor effects of supplemental oxygenation', Science Translational Medicine, vol. 7, no. 277. https://doi.org/10.1126/scitranslmed.aaa1260
Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B, Abbott R et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Science Translational Medicine. 2015 Mar 4;7(277). https://doi.org/10.1126/scitranslmed.aaa1260
Hatfield, Stephen M. ; Kjaergaard, Jorgen ; Lukashev, Dmitriy ; Schreiber, Taylor H. ; Belikoff, Bryan ; Abbott, Robert ; Sethumadhavan, Shalini ; Philbrook, Phaethon ; Ko, Kami ; Cannici, Ryan ; Thayer, Molly ; Rodig, Scott ; Kutok, Jeffrey L. ; Jackson, Edwin K. ; Karger, Barry ; Podack, Eckhard R. ; Ohta, Akio ; Sitkovsky, Michail V. / Immunological mechanisms of the antitumor effects of supplemental oxygenation. In: Science Translational Medicine. 2015 ; Vol. 7, No. 277.
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