期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 7, 期 277, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaa1260
关键词
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资金
- Northeastern University
- NIH [R01 CA 112561, R01 CA 111985, R21 AT 002788, U19 AI 091693]
- National Cancer Institute [5PO1CA109094-03]
- National Institute of Allergy and Infectious Diseases 1P01 grant [AI096396-01 3, HL109002, DK091190, DK068575, DK079307, CA168628]
- Bankhead-Coley Postdoctoral Fellowship
- NIH (Dana-Farber Cancer Institute)
- NIH (Harvard Medical School-Northeastern University Joint Program in Cancer Drug Development)
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-beta (TGF-beta), (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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