title: Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia.
abstract: Cancerous tissue protection from tumor-recognizing CD8(+) and CD4(+) T cells (antitumor T cells) limits the therapeutic potential of immunotherapies. We propose that tumor protection is to a large extent due to (a) inhibition of antitumor T cells by hypoxia-driven accumulation of extracellular adenosine in local tumor microenvironment and due to (b) T regulatory cell-produced extracellular adenosine. The adenosine triggers the immunosuppressive signaling via intracellular cyclic AMP-elevating A2A adenosine receptors (A2AR) on antitumor T cells. In addition, the activated antitumor T cells in hypoxic tumor microenvironment could be inhibited by elevated levels of immunosuppressive hypoxia-inducible factor-1alpha. Complete rejection or tumor growth retardation was observed when A2AR has been genetically eliminated or antagonized with synthetic drug or with natural A2AR antagonist 1,3,7-trimethylxanthine (caffeine). The promising strategy may be in combining the anti-hypoxia-adenosinergic treatment that prevents inhibition of antitumor T cells by tumor-produced and T regulatory cell-produced adenosine with targeting of other negative regulators, such as CTL antigen-4 blockade. Observations of tumor rejection in mice and massive prospective epidemiologic studies support the feasibility of anti-hypoxia-adenosinergic combined immunotherapy.
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. m.sitkovsky@neu.edu
authors.forename: Michail V
authors.initials: MV
authors.lastname: Sitkovsky
authors.forename: Jorgen
authors.initials: J
authors.lastname: Kjaergaard
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Lukashev
authors.forename: Akio
authors.initials: A
authors.lastname: Ohta
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D000241:Adenosine