Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy
Open accessAbstract
Hypoxia/HIF-1α- and extracellular adenosine/A2 adenosine receptor-mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune cells in hypoxic and extracellular adenosine-rich tumors that are the most resistant to current therapies. Here, we explain a potentially novel, antiimmunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of antihypoxic oxygenation described here was motivated by the need to prevent the hypoxia/HIF-1α-driven accumulation of extracellular adenosine to (a) unleash antitumor immune cells from inhibition by intracellular cAMP and (b) prevent immunosuppressive transcription of cAMP response element- and hypoxia response element-containing immunosuppressive gene products (e.g., TGF-β). Use of oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes of clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanism-based approach to cancer immunotherapy described here.
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Hypoxia induces increased expression of CD73, which mediates production of extracellular adenosine, which binds adenosine 2A receptors on T lymphocytes and NK cells, thereby suppressing antitumor immunity.
“hypoxia induces increased expression of CD73, the enzyme that mediates production of extracellular adenosine, which binds to adenosine 2A receptors on T lymphocytes and natural killer (NK) cells, thereby suppressing antitumor immunity (13, 17, 36).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [17]
Intratumoral hypoxia is a major driving force for cancer progression.
“Intratumoral hypoxia is a major driving force for cancer progression (15–19).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [17]
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- Authors
- Hatfield, S. M., & Sitkovsky, M. V.
- Affiliations
- Northeastern University (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2020-09-28
- Volume
- 130
- Issue
- 11
- Pages
- 5629-5637
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7598059
- OpenAlex
- W3082243091
- Cited by
- 73
- References
- 91
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 8 · 2022: 21 · 2021: 15 · 2020: 1
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- tumor hypoxia, HIF-1α, extracellular adenosine, adenosine A2A receptor, cancer immunotherapy, immunosuppression, cAMP signaling, TGF-beta, tumor oxygenation, combined radiotherapy
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Immunotherapy, Neoplasms, Oxygen, Hyperoxia
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