Immunological mechanisms of the antitumor effects of supplemental oxygenation
| Autor: | Dmitriy Lukashev, Jeffrey L. Kutok, Shalini Sethumadhavan, Phaethon Philbrook, Michail V. Sitkovsky, Bryan Belikoff, Barry L. Karger, Ryan Cannici, Jorgen Kjaergaard, Robert K. Abbott, Eckhard R. Podack, Taylor H. Schreiber, Stephen M. Hatfield, Akio Ohta, Molly Thayer, Kami Ko, Scott J. Rodig, Edwin K. Jackson |
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| Rok vydání: | 2015 |
| Předmět: |
Adenosine
medicine.medical_treatment T cell chemical and pharmacologic phenomena Antineoplastic Agents Hyperoxia Biology T-Lymphocytes Regulatory Article Proinflammatory cytokine Cancer immunotherapy Cell Line Tumor Neoplasms Tumor Microenvironment medicine Animals Humans Cytotoxic T cell Neoplasm Metastasis Hypoxia Immunosuppression Therapy Mice Inbred BALB C Tumor microenvironment Respiration Remission Induction Immunosuppression General Medicine Killer Cells Natural Mice Inbred C57BL Oxygen Disease Models Animal medicine.anatomical_structure Immunology Cancer research Female medicine.symptom medicine.drug |
| Zdroj: | Science Translational Medicine. 7 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aaa1260 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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