Cited by 73Cancer, Hypoxia, and MetabolismAdenosine and Purinergic SignalingCancer Immunotherapy and Biomarkers

Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy

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Hatfield, Stephen M., Sitkovsky, Michail V.·2020·Journal of Clinical Investigation

Abstract

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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  1. Sheridan C. Adorx dives into the adenosine antagonism pool with $10M series A. BioWorld. 2018;29(121):1-6.

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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
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
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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