Immunological mechanisms of the antitumor effects of supplemental oxygenation

Sci Transl Med. 2015 Mar 4;7(277):277ra30. doi: 10.1126/scitranslmed.aaa1260.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Hyperoxia / complications
  • Hyperoxia / pathology
  • Hypoxia / complications
  • Hypoxia / immunology
  • Hypoxia / pathology
  • Immunosuppression
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Oxygen / pharmacology
  • Oxygen / therapeutic use*
  • Remission Induction
  • Respiration / drug effects
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents
  • Adenosine
  • Oxygen