A2A Adenosine Receptor Protects Tumors from Antitumor T Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 35; pp. 13132 - 13137
• Main Authors: Ohta, Akio, Gorelik, Elieser, Prasad, Simon J., Ronchese, Franca, Lukashev, Dmitriy, Wong, Michael K. K., Huang, Xiaojun, Caldwell, Sheila, Liu, Kebin, Smith, Patrick, Chen, Jiang-Fan, Jackson, Edwin K., Apasov, Sergey, Abrams, Scott, Sitkovsky, Michail
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.08.2006; National Acad Sciences
• Subjects: Adenosine; Adenosine - metabolism; Adenosine A2 Receptor Antagonists; Animals; Biological Sciences; Cancer; CD8-Positive T-Lymphocytes - immunology; Cell growth; Cell- and Tissue-Based Therapy; Humans; Hypoxia; Immunity (Disease); Immunotherapy, Adoptive; Inoculation; Interferon-gamma - biosynthesis; Lungs; Melanoma; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mutation - genetics; Purinergic P1 receptors; Receptor, Adenosine A2A - deficiency; Receptor, Adenosine A2A - metabolism; Rodents; T cell receptors; T lymphocytes; Tissues; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0605251103

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 A2ARdeficient 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.