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Etiology and Pathogenesis > Hypoxia / Inflammation / Immune Response

Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0605251103, Published online before print August 17, 2006

Abstract
A2A adenosine receptor protects tumors from antitumor T cells

Akio Ohta1,2, Elieser Gorelik3, Simon J. Prasad4, Franca Ronchese4, Dmitriy Lukashev1,2, Michael K. K. Wong3,5, Xiaojun Huang3, Sheila Caldwell6, Kebin Liu6,7, Patrick Smith1, Jiang-Fan Chen8, Edwin K. Jackson9, Sergey Apasov1, Scott Abrams6, and Michail Sitkovsky1,2,*

1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; 2New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115; 3Department of Pathology and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213; 4Malaghan Institute of Medical Research, Wellington, New Zealand; 5Department of Medicine and Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263; 6Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; 7Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912; 8Department of Neurology, Boston University School of Medicine, Boston, MA 02118; and 9Center for Clinical Pharmacology, Departments of Pharmacology and Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213 -- *To whom correspondence should be addressed at: New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113 Mugar Life Sciences Building, Boston, MA 02115. Michail Sitkovsky, E-mail: m.sitkovsky@neu.edu -- Communicated by William E. Paul, National Institutes of Health, Bethesda, MD, June 22, 2006 (received for review March 29, 2006).


The A2A adenosine receptor (A2AR) has been shown to be a critical and nonredundant negative regulator of immune cells in protecting normal tissues from inflammatory damage. 
We hypothesized that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. 
Here we confirm this hypothesis by showing that genetic deletion of A2AR in the host resulted in rejection of established immunogenic tumors in ≈60% of A2AR-deficient mice with no rejection observed in control WT mice. 
The use of antagonists, including caffeine, or targeting the A2 receptors by siRNA pretreatment of T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neovascularization by antitumor T cells. 
The data suggest that effects of A2AR are T cell autonomous. 
The inhibition of antitumor T cells via their A2AR in the adenosine-rich tumor microenvironment may explain the paradoxical coexistence of tumors and antitumor immune cells in some cancer patients (the "Hellstrom paradox"). 
We propose to target the hypoxia→adenosine→A2AR pathway as a cancer immunotherapy strategy to prevent the inhibition of antitumor T cells in the tumor microenvironment. 
The same strategy may prevent the premature termination of immune response and improve the vaccine-induced development of antitumor and antiviral T cells. 
The observations of autoimmunity during melanoma rejection in A2AR-deficient mice suggest that A2AR in T cells is also important in preventing autoimmunity. 
Thus, although using the hypoxia→adenosine→A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.

Keywords: autoimmunity; cancer; therapy; hypoxia; inflammation


Copyright © 2006 by the National Academy of Sciences
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