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Session IV: Modulators of Immune Escape Mechanisms

The hypoxia-adenosinergic protection of tumors from anti-tumor T lymphocytes

Michail V. Sitkovsky
Michail V. Sitkovsky
New England Inflammation and Tissue Protection Institute, a Consortium at Northeastern University and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, MA, USA
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DOI:  Published January 2008
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Abstract

Cancer immunotherapy by endogenous or adoptively transferred anti-tumor T cells is complementary to conventional treatments by surgery, radiotherapy, or chemotherapy. However, malignant cells can create a self-protective, immunosuppressive tumor microenvironment (TME) that prevents tumor destruction by anti-tumor T cells.

During last three decades we considered the possibility that cancerous tissues are protected by the same ancient, physiological tissue-protecting mechanism that has evolved to protect inflamed areas of normal tissues from continuing collateral damage during anti-pathogen immune response. Subsequent studies of T cell-mediated tumor rejection and of in vivo anti-pathogen immune response supported this view (1, 2).

Hypoxia-adenosinergic inhibition of anti-tumor T lymphocytes by A2 adenosine receptors and hypoxia-inducible factors This tissue-protecting, negative feedback immunosuppressive mechanism is triggered by excessive tissue damage-associated interruption of local blood and oxygen supply, which results in local tissue hypoxia, stabilization of the Hypoxia Inducible Factors and hypoxia-driven accumulation of extracellular adenosine (3).

The extracellular adenosine then signals via high affinity A2A and low affinity A2B adenosine receptors on the surface of CD8+ and CD4+ T cells and thereby elevates intracellular levels of highly immunosuppressive cAMP. The "Adenosinergic" signaling inhibits the TCR-triggered activation of T cells and of their many effector functions (4, 5).

The Hypoxia-Inducible Factor 1alpha and its isoforms may function to inhibit the T cells "from inside" as suggested by experiments using RAG-2-/- blastocyst complementation chimeras and by in vitro and in vivo studies using tissue-specific deletion of HIF-1alpha gene in T cells (6, 7).

Indeed, some areas of cancerous tissues and of inflamed normal tissues are, indeed, hypoxic and extracellular adenosine-rich (2), although for different reasons. While inflamed tissues areas are hypoxic due to the excessive collateral immune damage to vasculature, some areas of tumors are hypoxic either because of abnormal cancerous tissue infrastructure and/or geometry or because the tumor growth outpaces the growth of supporting vascular bed.

Anti-hypoxia-adenosinergic cancer immunotherapy strategy The A2A adenosine receptors on the surface of anti-tumor CD8+ T cells strongly inhibit T cellmediated tumor rejection since genetic deletion or pharmacological antagonism improved T cell-mediated tumor rejection (2). Thus, while the Hypoxia-Adenosinergic inhibition of overactive T cells during acute inflammation protects tissues of vital organs and is life-saving, the Hypoxia-Adenosinergic inhibition of anti-tumor T cells in TME protects tumors and is to be prevented.

We provided the genetic in vivo evidence that one of the approaches to prevent the inhibition of cancer vaccine-induced and endogenously developed or adoptively transferred anti-tumor T cells is to weaken or eliminate the Hypoxia-Adenosinergic signaling. This "Anti-Hypoxia-Adenosinergic" approach may add to the already demonstrated promise of targeting other negative regulators of anti-tumor immune response, such as e.g. CTLA4 and Tregs (8).

We plan to improve tumor rejection by preventing the Hypoxia-Adenosinergic inhibition of anti-tumor T cells by (a) using the A2AR antagonist drug (synthetic or natural compounds) that out-competes the tumor-produced and T cell-inhibiting extracellular adenosine in TME and by (b) treatments that decrease the levels of tumor-produced adenosine and thereby enable the competitive A2AR antagonist to be more effective. The one of unusual features of this approach is in the opportunity to immediately test effects of the non-selective A2A adenosine receptor antagonist 1,3,7-trimethylxanthine (a.k.a. caffeine). The caffeine is the most widely used psychoactive drug in the world with quite acceptable toxicity in humans. In vivo preclinical studies suggest that even better immunotherapeutic effects could be expected with longer-lived in vivo synthetic A2A receptor antagonists which have been developed for Parkinson disease and shown to be safe in human clinical trials.

This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.

 

  • Copyright © 2008 by Michail V. Sitkovsky

References

  1. 1.↵
    1. Ohta A,
    2. Sitkovsky M
    . Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 2001;414:916–920.pmid:11780065
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    . A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 2006;103:13132–13137.pmid:16916931
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Sitkovsky M,
    2. Lukashev D
    . Regulation of immune cells by local-tissue oxygen tension: HIF1alpha and adenosine receptors. Nat Rev Immunol 2005;5:712–721.pmid:16110315
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Huang S,
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    3. Koshiba M,
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    . Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 1997;90:1600–1610.pmid:9269779
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Koshiba M,
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    . Memory of extracellular adenosine/A2a purinergic receptor-mediated signaling in murine T cells. J Biol Chem 1997;272:25881–25889.pmid:9325320
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  6. 6.↵
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    . Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci U S A 2002;99:2170–2174.pmid:11854513
    OpenUrlAbstract/FREE Full Text
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    1. Lukashev D,
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    . Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 2006;177:4962–4965.pmid:17015677
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Hodi FS,
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    19. Mihm MC,
    20. Dranoff G
    . Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008;105:3005–3010.pmid:18287062
    OpenUrlAbstract/FREE Full Text
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Cancer Immunity Archive: 8 (Suppl 2)
January 2008
Volume 8, Issue Suppl 2
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The hypoxia-adenosinergic protection of tumors from anti-tumor T lymphocytes
Michail V. Sitkovsky
Cancer Immun January 1 2008 (8) (Suppl 2) 17;

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The hypoxia-adenosinergic protection of tumors from anti-tumor T lymphocytes
Michail V. Sitkovsky
Cancer Immun January 1 2008 (8) (Suppl 2) 17;
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