A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment

Abstract

Within tumors, some areas are less oxygenated than others. Since their home ground is under chronic hypoxia, tumor cells adapt to this condition by activating aerobic glycolysis; however, this hypoxic environment is very harsh for incoming immune cells. Deprivation of oxygen limits availability of energy sources and induces accumulation of extracellular adenosine in tumors. Extracellular adenosine, upon binding with adenosine receptors on the surface of various immune cells, suppresses pro-inflammatory activities. In addition, signaling through adenosine receptors upregulates a number of anti-inflammatory molecules and immunoregulatory cells, leading to the establishment of a long-lasting immunosuppressive environment. Thus, due to hypoxia and adenosine, tumors can discourage antitumor immune responses no matter how the response was induced, whether it was spontaneous or artificially introduced with a therapeutic intention. Preclinical studies have shown the significance of adenosine in tumor survival strategy by demonstrating tumor regression after inactivation of adenosine receptors, inhibition of adenosine-producing enzymes, or reversal of tissue hypoxia. These promising results indicate a potential use of the inhibitors of the hypoxia-adenosine pathway for cancer immunotherapy.

Keywords: A2A adenosine receptor; CD73; adenosine; cancer immunotherapy; immune checkpoint; immunosuppression; tissue hypoxia; tumor microenvironment.

Figure 1

Pro-cancer activities of extracellular adenosine and therapeutic targets for improvement of cancer immunotherapy. Tissue hypoxia in tumors increases extracellular adenosine production through induction of CD39 and CD73. Produced adenosine transmits immunosuppressive signals through adenosine receptors on various immune cells. A2AR stimulation in effector T cells (Teff) blocks T cell receptor signaling and impairs effector functions including IFN-γ production and cytotoxicity. In antigen-presenting cells (APC), signals through A2AR and A2BR reduce Th1-type cytokine milieu and induce tolerogenic APC. Interaction of Teff with these APC will impair activation of cellular immune response against cancer cells. Adenosine enhances immunoregulatory activity of regulatory T cells (Treg). The qualitative and quantitative increase of Treg results in stronger inactivation of antitumor immune response. In addition, adenosine can promote proliferation, survival and metastatic activity of cancer cells. Suppression of adenosine pathway will be able to weaken the intensity of immunosuppression in tumor microenvironment and direct effect on cancer cells. Potential target molecules are adenosine receptors (A2AR and A2BR) and adenosine-producing enzymes (CD39 and CD73). Oxygen supplementation can also decrease pro-cancer effects of adenosine as well as adenosine-independent immunosuppression by hypoxia.