Immunological mechanisms of the antitumor effects of supplemental oxygenation
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Respiratory hyperoxia stimulates lung tumor regression by promoting T cell infiltration into the tumors and decreasing immunosuppression.
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In mouse models, hypoxic zones within tumors lack T cells.
“In mouse models, hypoxic zones within tumors were shown to lack T cells (37, 38).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [37]
The Results section reports markedly fewer CD4 and CD8 T cells in hypoxic tumor areas than in neighboring normoxic areas in mouse models. It does not say those areas lack T cells entirely. No page number is provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExposing tumor-bearing mice to an ambient O2 concentration of 60% was sufficient to alter the tumor microenvironment from immunosuppression to antitumor immunity.
“The critical role of intratumoral hypoxia as the stimulus for immunosuppression was also demonstrated by exposing tumor-bearing mice to an ambient O2 concentration of 60%, which was sufficient to alter the tumor microenvironment from immunosuppression to antitumor immunity (37).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [37]
In solid tumors, tumor hypoxia and HIF-1α promote the upregulation of adenosine-producing enzymes, such as CD39/CD73, which can dephosphorylate ATP to adenosine.
“In solid tumors, tumor hypoxia and HIF‐1α promote the upregulation of adenosine‐producing enzymes, such as CD39/CD73, which can dephosphorylate ATP to adenosine.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [206]
Increased tumor oxygenation may directly disrupt adenosine-mediated immunosuppression by inhibiting the enzymatic activity of CD39 and CD73 to block adenosine production.
“Increased tumor oxygenation may directly disrupt adenosine‐mediated immunosuppression by inhibiting the enzymatic activity of CD39 and CD73 to block adenosine production (Figure 6A). 206”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [206]
High concentrations of oxygen activate the anticancer effects of T cells and NK cells by deactivating the adenosine immunosuppressive microenvironment.
“High concentrations of oxygen activate the anticancer effects of T cells and NK cells by deactivating the adenosine immunosuppressive microenvironment. 127 , 206 , 408”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [206]
Respiratory hyperoxia is associated with a decrease in intratumoral hypoxia and an immunopermissive tumor microenvironment characterized by abundant CD8+ T cell infiltration and decreased regulatory T cell infiltration.
“respiratory hyperoxia was associated with a decrease in intratumoral hypoxia and an immunopermissive tumor microenvironment characterized by abundant CD8+ T cell infiltration and decreased regulatory T cell infiltration”
From Hypoxic control of metastasis (2016) · cites this paper as [50]
In preclinical models, respiratory hyperoxia (60% O2) can promote tumor regression, reduce metastatic disease, and prolong animal survival.
“In preclinical models, respiratory hyperoxia (60% O2) can promote tumor regression, reduce metastatic disease, and prolong animal survival”
From Hypoxic control of metastasis (2016) · cites this paper as [50]
Targeting HIF-1α in immunotherapy is a relatively new concept, for which proof of principle has been amply demonstrated by others.
“Targeting HIF-1α in immunotherapy is a relatively new concept, for which proof of principle has been amply demonstrated by others (12, 23, 27).”
From Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues (2022) · cites this paper as [27]
Direct elimination of TME hypoxia can improve cancer immunotherapy in mice.
“Subsequently, it was shown that direct elimination of TME hypoxia can improve cancer immunotherapy in mice (27, 38, 39).”
From Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues (2022) · cites this paper as [27]
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Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy
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- Authors
- Hatfield, S. M., Kjaergaard, J., Lukashev, D., Schreiber, T. H., Belikoff, B., Abbott, R., Sethumadhavan, S., Philbrook, P., Ko, K., Cannici, R., Thayer, M., Rodig, S., Kutok, J. L., Jackson, E. K., Karger, B., Podack, E. R., Ohta, A., & Sitkovsky, M. V.
- Affiliations
- Northeastern University (US)
- New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
- University of Miami (US)
- Brigham and Women's Hospital (US)
- University of Pittsburgh (US)
- Corresponding author
- Schreiber, Taylor H.
- Kutok, Jeffrey L.
- Sitkovsky, Michail V.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2015-03-04
- Volume
- 7
- Issue
- 277
- Pages
- 277ra30-277ra30
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4641038
- OpenAlex
- W1987534017
- Cited by
- 600
- References
- 53
- Citations by year
- 2026: 31 · 2025: 46 · 2024: 51 · 2023: 68 · 2022: 72 · 2021: 81 · 2020: 74 · 2019: 49 · 2018: 40 · 2017: 31 · 2016: 35 · 2015: 21
- FWCI
- 35.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- 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 (AI096396-01 3, HL109002, DK091190, DK068575, DK079307, CA168628)
- Bankhead-Coley Postdoctoral Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- supplemental oxygen, hyperoxia, tumor microenvironment, tumor hypoxia, extracellular adenosine, adenosine A2A receptor, immunosuppression, CD8+ T cells, regulatory T cells, TGF-beta, natural killer cells, breast cancer metastasis
- MeSH terms
- Adenosine, Animals, Hypoxia, Antineoplastic Agents, Disease Models, Animal, Female, Humans, Immunosuppression Therapy, Killer Cells, Natural, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms, Oxygen, Remission Induction, Respiration, Hyperoxia, Cell Line, Tumor, T-Lymphocytes, Regulatory, Tumor Microenvironment
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