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Hypoxia and Cancer Metastasis pp 113–121Cite as

Mechanistic Justifications of Systemic Therapeutic Oxygenation of Tumors to Weaken the Hypoxia Inducible Factor 1α-Mediated Immunosuppression

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1136))

Abstract

Long-term studies of anti-pathogen and anti-tumor immunity have provided complementary genetic and pharmacological evidence for the immunosuppressive and immunomodulatory effects of Hypoxia-HIF-1α and adenosine-mediated suppression via the A2A adenosine receptor signaling pathway (Hypoxia-A2A-adenosinergic). This pathway is life saving when it protects inflamed tissues of vital organs from collateral damage by overactive anti-pathogen immune cells or enables the differentiation of cells of adaptive immunity. However, the Hypoxia-A2A-adenosinergic immunosuppression can also prevent tumor rejection by inhibiting the anti-tumor effects of T and NK cells. In addition, this suppressive pathway has been shown to mask tumors due to the hypoxia-HIF-α-mediated loss of MHC Class I molecules on tumor cells. It is suggested that it will be impossible to realize the full anti-tumor capacities of current cancer immunotherapies without simultaneous administration of anti-Hypoxia-A2A-Adenosinergic drugs that inactivate this tumor-protecting mechanism in hypoxic and adenosine-rich tumors.

Here, we overview the supporting evidence for the conceptually novel immunotherapeutic motivation to breathe supplemental oxygen (40–60%) or to repurpose already available oxygenation agents in combination with current immunotherapies. Preclinical studies provide strong support for oxygen immunotherapy to enable much stronger tumor regression by weakening immunosuppression by A2A adenosine receptors and by the Hypoxia➔HIF-1α axis. The results of these studies emphasize the value of systemic oxygenation as clinically feasible, promising, and as a valuable tool for mechanistic investigations of tumor biology and cancer immunology. Perhaps the most effective and feasible among individual members of this novel class of anti-tumor drugs are oxygenation agents.

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Authors and Affiliations

  1. New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, USA

    Stephen Hatfield, Katarina Veszeleiova, Joe Steingold, Jyothi Sethuraman & Michail Sitkovsky

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  1. Stephen Hatfield
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  2. Katarina Veszeleiova
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  3. Joe Steingold
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  4. Jyothi Sethuraman
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  5. Michail Sitkovsky
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Corresponding author

Correspondence to Michail Sitkovsky .

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Editors and Affiliations

  1. Breast and Ovarian Cancer Program, Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniele M. Gilkes

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Hatfield, S., Veszeleiova, K., Steingold, J., Sethuraman, J., Sitkovsky, M. (2019). Mechanistic Justifications of Systemic Therapeutic Oxygenation of Tumors to Weaken the Hypoxia Inducible Factor 1α-Mediated Immunosuppression. In: Gilkes, D. (eds) Hypoxia and Cancer Metastasis. Advances in Experimental Medicine and Biology, vol 1136. Springer, Cham. https://doi.org/10.1007/978-3-030-12734-3_8

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