Immunological mechanisms of the antitumor effects of supplemental oxygenation.
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.
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Stephen M
SM
Hatfield
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Jorgen
J
Kjaergaard
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Dmitriy
D
Lukashev
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Taylor H
TH
Schreiber
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Bryan
B
Belikoff
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Robert
R
Abbott
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Shalini
S
Sethumadhavan
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Phaethon
P
Philbrook
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Kami
K
Ko
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Ryan
R
Cannici
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Molly
M
Thayer
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, MA 02115, USA.
Scott
S
Rodig
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, MA 02115, USA.
Jeffrey L
JL
Kutok
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Edwin K
EK
Jackson
Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA 02115, USA.
Barry
B
Karger
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Eckhard R
ER
Podack
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Akio
A
Ohta
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Institutes of Medicine, 44 Binney Street, Boston, MA 02115, USA. m.sitkovsky@neu.edu.
Michail V
MV
Sitkovsky
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000150:complications / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000276:immunology / Q000473:pathology; D007165:Immunosuppression Therapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology / Q000627:therapeutic use*; D012074:Remission Induction; D012119:Respiration / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects
D000970:Antineoplastic Agents; D000241:Adenosine; D010100:Oxygen