Skip to main content

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

  • Chapter
  • First Online:
Hypoxia and Cancer Metastasis

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414(6866):916–920

    Article  CAS  Google Scholar 

  2. Kojima H et al (2002) Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci USA 99(4):2170–2174

    Article  CAS  Google Scholar 

  3. Ohta A et al (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 103(35):13132–13137

    Article  CAS  Google Scholar 

  4. Sitkovsky MV et al (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22:657–682

    Article  CAS  Google Scholar 

  5. Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5(9):712–721

    Article  CAS  Google Scholar 

  6. Sitkovsky MV et al (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14(19):5947–5952

    Article  CAS  Google Scholar 

  7. Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30(3):102–108

    Article  CAS  Google Scholar 

  8. Hatfield SM et al (2014) Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1alpha-dependent and extracellular adenosine-mediated tumor protection. J Mol Med (Berl) 92:1283–1292

    Article  CAS  Google Scholar 

  9. Hatfield SM et al (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7(277):277ra30

    Article  CAS  Google Scholar 

  10. Kjaergaard J et al (2018) A2A adenosine receptor gene deletion or synthetic A2A antagonist liberate tumor-reactive CD8(+) T cells from tumor-induced immunosuppression. J Immunol 201(2):782–791

    Article  CAS  Google Scholar 

  11. Eltzschig HK, Sitkovsky MV, Robson SC (2013) Purinergic signaling during inflammation. N Engl J Med 368(13):1260

    CAS  PubMed  Google Scholar 

  12. Sitkovsky MV et al (2014) Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2(7):598–605

    Article  CAS  Google Scholar 

  13. Cronstein BN, Sitkovsky M (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13(1):41–51

    Article  CAS  Google Scholar 

  14. Kojima H et al (2010) Differentiation stage-specific requirement in hypoxia-inducible factor-1alpha-regulated glycolytic pathway during murine B cell development in bone marrow. J Immunol 184(1):154–163

    Article  CAS  Google Scholar 

  15. Abbott RK et al (2016) Germinal center hypoxia potentiates immunoglobulin class switch recombination. J Immunol 197(10):4014–4020

    Article  CAS  Google Scholar 

  16. Abbott RK et al (2017) The GS protein-coupled A2a adenosine receptor controls T cell help in the germinal center. J Biol Chem 292(4):1211–1217

    Article  CAS  Google Scholar 

  17. Stagg J et al (2011) CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 71(8):2892–2900

    Article  CAS  Google Scholar 

  18. Stagg J et al (2012) CD73-deficient mice are resistant to carcinogenesis. Cancer Res 72(9):2190–2196

    Article  CAS  Google Scholar 

  19. Allard B et al (2013) Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 19(20):5626–5635

    Article  CAS  Google Scholar 

  20. Loi S et al (2013) CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci USA 110(27):11091–11096

    Article  CAS  Google Scholar 

  21. Jin D et al (2010) CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res

    Google Scholar 

  22. Zhang B (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70(16):6407–6411

    Article  CAS  Google Scholar 

  23. Deaglio S et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265

    Article  CAS  Google Scholar 

  24. Chouker A et al (2008) Critical role of hypoxia and A2A adenosine receptors in liver tissue-protecting physiological anti-inflammatory pathway. Mol Med 14(3–4):116–123

    Article  CAS  Google Scholar 

  25. Thiel M et al (2005) Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3(6):e174

    Article  Google Scholar 

  26. Semenza GL (2014) Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol 76:39–56

    Article  CAS  Google Scholar 

  27. Synnestvedt K et al (2002) Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 110(7):993–1002

    Article  CAS  Google Scholar 

  28. Thiel M et al (2007) Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS One 2(9):e853

    Article  Google Scholar 

  29. Buras JA, Holzmann B, Sitkovsky M (2005) Animal models of sepsis: setting the stage. Nat Rev Drug Discov 4(10):854–865

    Article  CAS  Google Scholar 

  30. Georgiev P et al (2013) Genetic deletion of the HIF-1alpha isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model. Eur J Immunol 43(3):655–666

    Article  CAS  Google Scholar 

  31. Lukashev D, Sitkovsky M (2008) Preferential expression of the novel alternative isoform I.3 of hypoxia-inducible factor 1alpha in activated human T lymphocytes. Hum Immunol 69(7):421–425

    Article  CAS  Google Scholar 

  32. Hatfield SM, Sitkovsky M (2015) Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators. Oncoimmunology 4(12):e1052934

    Article  Google Scholar 

  33. Sethumadhavan S et al (2017) Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells. PLoS One 12(11):e0187314

    Article  Google Scholar 

  34. Zarek PE et al (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111(1):251–259

    Article  CAS  Google Scholar 

  35. Leone RD et al (2018) Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models. Cancer Immunol Immunother 67:1271–1284

    Article  CAS  Google Scholar 

  36. Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of Cancer progression. Trends Cancer 2(12):758–770

    Article  Google Scholar 

  37. Xiang L et al (2014) Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer. J Mol Med (Berl) 92(2):151–164

    Article  CAS  Google Scholar 

  38. Hubbi ME et al (2012) Four-and-a-half LIM domain proteins inhibit transactivation by hypoxia-inducible factor 1. J Biol Chem 287(9):6139–6149

    Article  CAS  Google Scholar 

  39. Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57(13):2602–2605

    CAS  PubMed  Google Scholar 

  40. Sittler T et al (2008) Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunity. Clin Cancer Res 14(12):3896–3905

    Article  CAS  Google Scholar 

  41. Takayama H, Sitkovsky MV (1988) Potential use of antagonists of cAMP-dependent protein kinase to block inhibition and modulate T-cell receptor-triggered activation of cytotoxic T-lymphocytes. J Pharm Sci 78:8–10

    Article  Google Scholar 

  42. Armstrong JM et al (2001) Gene dose effect reveals no Gs-coupled A2A adenosine receptor reserve in murine T-lymphocytes: studies of cells from A2A-receptor-gene- deficient mice. Biochem J 354(Pt 1):123–130

    Article  CAS  Google Scholar 

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

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michail Sitkovsky .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

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

Download citation

Publish with us

Policies and ethics