Advertisement

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

  • Stephen Hatfield
  • Katarina Veszeleiova
  • Joe Steingold
  • Jyothi Sethuraman
  • Michail SitkovskyEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Hypoxia Hypoxia-inducible factor-1α HIF-1α Hypoxia reduction Oxygen Oxygenation agents Supplemental oxygenation Cancer immunotherapy Tumor microenvironment Adenosine A2A adenosine receptor (A2AR) Cyclic AMP (cAMP) T cells Natural killer cells 

References

  1. 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):916–920CrossRefGoogle Scholar
  2. 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):2170–2174CrossRefGoogle Scholar
  3. 3.
    Ohta A et al (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 103(35):13132–13137CrossRefGoogle Scholar
  4. 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 22:657–682CrossRefGoogle Scholar
  5. 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):712–721CrossRefGoogle Scholar
  6. 6.
    Sitkovsky MV et al (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14(19):5947–5952CrossRefGoogle Scholar
  7. 7.
    Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30(3):102–108CrossRefGoogle Scholar
  8. 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) 92:1283–1292CrossRefGoogle Scholar
  9. 9.
    Hatfield SM et al (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7(277):277ra30CrossRefGoogle Scholar
  10. 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):782–791CrossRefGoogle Scholar
  11. 11.
    Eltzschig HK, Sitkovsky MV, Robson SC (2013) Purinergic signaling during inflammation. N Engl J Med 368(13):1260PubMedGoogle Scholar
  12. 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):598–605CrossRefGoogle Scholar
  13. 13.
    Cronstein BN, Sitkovsky M (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13(1):41–51CrossRefGoogle Scholar
  14. 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):154–163CrossRefGoogle Scholar
  15. 15.
    Abbott RK et al (2016) Germinal center hypoxia potentiates immunoglobulin class switch recombination. J Immunol 197(10):4014–4020CrossRefGoogle Scholar
  16. 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):1211–1217CrossRefGoogle Scholar
  17. 17.
    Stagg J et al (2011) CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 71(8):2892–2900CrossRefGoogle Scholar
  18. 18.
    Stagg J et al (2012) CD73-deficient mice are resistant to carcinogenesis. Cancer Res 72(9):2190–2196CrossRefGoogle Scholar
  19. 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):5626–5635CrossRefGoogle Scholar
  20. 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):11091–11096CrossRefGoogle Scholar
  21. 21.
    Jin D et al (2010) CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer ResGoogle Scholar
  22. 22.
    Zhang B (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70(16):6407–6411CrossRefGoogle Scholar
  23. 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):1257–1265CrossRefGoogle Scholar
  24. 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):116–123CrossRefGoogle Scholar
  25. 25.
    Thiel M et al (2005) Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3(6):e174CrossRefGoogle Scholar
  26. 26.
    Semenza GL (2014) Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol 76:39–56CrossRefGoogle Scholar
  27. 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):993–1002CrossRefGoogle Scholar
  28. 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):e853CrossRefGoogle Scholar
  29. 29.
    Buras JA, Holzmann B, Sitkovsky M (2005) Animal models of sepsis: setting the stage. Nat Rev Drug Discov 4(10):854–865CrossRefGoogle Scholar
  30. 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):655–666CrossRefGoogle Scholar
  31. 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):421–425CrossRefGoogle Scholar
  32. 32.
    Hatfield SM, Sitkovsky M (2015) Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators. Oncoimmunology 4(12):e1052934CrossRefGoogle Scholar
  33. 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):e0187314CrossRefGoogle Scholar
  34. 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):251–259CrossRefGoogle Scholar
  35. 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 67:1271–1284CrossRefGoogle Scholar
  36. 36.
    Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of Cancer progression. Trends Cancer 2(12):758–770CrossRefGoogle Scholar
  37. 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):151–164CrossRefGoogle Scholar
  38. 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):6139–6149CrossRefGoogle Scholar
  39. 39.
    Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57(13):2602–2605PubMedGoogle Scholar
  40. 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):3896–3905CrossRefGoogle Scholar
  41. 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 78:8–10CrossRefGoogle Scholar
  42. 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):123–130CrossRefGoogle Scholar
  43. 43.
    Sheridan C (2018) Adorx dives into the adenosine antagonism pool with $10M series A. BioWorld 29(121):1–6Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Stephen Hatfield
    • 1
  • Katarina Veszeleiova
    • 1
  • Joe Steingold
    • 1
  • Jyothi Sethuraman
    • 1
  • Michail Sitkovsky
    • 1
    Email author
  1. 1.New England Inflammation and Tissue Protection InstituteNortheastern UniversityBostonUSA

Personalised recommendations