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Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy
Stephen M. Hatfield, Michail V. Sitkovsky
Stephen M. Hatfield, Michail V. Sitkovsky
Published September 1, 2020
Citation Information: J Clin Invest. 2020;130(11):5629-5637. https://doi.org/10.1172/JCI137554.
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Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy

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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.

Authors

Stephen M. Hatfield, Michail V. Sitkovsky

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Figure 1

Immunosuppressive hypoxia/adenosinergic pathway in tumors and strategies for therapeutic targeting.

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Immunosuppressive hypoxia/adenosinergic pathway in tumors and strategies...
(A) Tumor hypoxia–driven accumulation of extracellular adenosine inhibits tumor-reactive T cells via A2A/A2B adenosine receptors. Tumor hypoxia (blue) stabilizes HIF-1α, increasing transcription of adenosine-generating ectoenzymes (e.g., CD39 and CD73), whose gene promoters contain hypoxia response elements (HREs). Adenosine binds to cAMP-elevating A2AR/A2BR on the surface of T cells, initiating protein kinase A–mediated (PKA-mediated) signaling cascades and resulting in the inhibition of T cell effector functions and immunosuppressive transcription via cAMP response elements (CREs). HIF-1α may synergize with cAMP signaling by directly inhibiting T cell effector functions and promoting immunosuppressive transcription via HREs. (B) Strategies targeting upstream and downstream stages of hypoxia/A2-adenosinergic immunosuppression in the TME. Oxygen/oxygenation agents restore physiological oxygen levels (physioxia) within the tumor, leading to oxygen-dependent degradation of HIF-1α. At the level of T cells, oxygenation therapy–induced reductions in HIF-1α also promote restoration of effector functions. A2AR/A2BR antagonists block the adenosinergic signaling that triggers CRE-mediated immunosuppressive transcription.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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