A2A adenosine receptor protects tumors from antitumor T cells.
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 approximately 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.
Ohta
Akio
A
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Gorelik
Elieser
E
Prasad
Simon J
SJ
Ronchese
Franca
F
Lukashev
Dmitriy
D
Wong
Michael K K
MK
Huang
Xiaojun
X
Caldwell
Sheila
S
Liu
Kebin
K
Smith
Patrick
P
Chen
Jiang-Fan
JF
Jackson
Edwin K
EK
Apasov
Sergey
S
Abrams
Scott
S
Sitkovsky
Michail
M
D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D064987:Cell- and Tissue-Based Therapy; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000378:metabolism*
D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D007371:Interferon-gamma; D000241:Adenosine