Research ArticleCancer

Immunological mechanisms of the antitumor effects of supplemental oxygenation

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Science Translational Medicine  04 Mar 2015:
Vol. 7, Issue 277, pp. 277ra30
DOI: 10.1126/scitranslmed.aaa1260

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Paving the way for intratumoral T cells

Tumors often express unusual antigens and are surrounded by immune cells. Unfortunately, this immune surveillance is imperfect and does not always prevent the tumors from growing. In addition, tumors are often hypoxic, because their rapid growth outstrips that of their blood and oxygen supply. Now, Hatfield et al. have linked these two phenomena by demonstrating that T cells avoid going into the hypoxic areas of tumors. The authors have also shown a way to overcome this problem in mice with lung tumors by having the animals breathe supplementary oxygen. Having a higher concentration of oxygen throughout the body improved the oxygenation inside the tumors, allowing immune cells to enter the tumors and attack them, extending the animals’ survival.

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.

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