Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer

Abstract

The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also underscored the need to better understand the mechanisms that prevent tumor rejection and survival even after the blockade of immunological negative regulators. Here, we describe the implications of the "metabolism-based" immunosuppressive mechanism, where the local tissue hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2 adenosine receptors on the surface of activated immune cells. This molecular pathway is of critical importance in mechanisms of immunosuppression in inflamed and cancerous tissue microenvironments. The protection of tumors by tumor-generated extracellular adenosine and A2 adenosine receptors could be the misguided application of the normal tissue-protecting mechanism that limits excessive collateral damage to vital organs during the anti-pathogen immune response. The overview of the current state of the art regarding the immunosuppressive effects of extracellular adenosine is followed by a historical perspective of studies focused on the elucidation of the physiological negative regulators that protect tissues of vital organs from excessive collateral damage, but, as a trade-off, may also weaken the anti-pathogen effector functions and negate the attempts of anti-tumor immune cells to destroy cancerous cells.

Figure 1

Improvement of anti-tumor immune responses by preventing immunosuppressive effects from the adenosine-A2AR pathway. Extracellular levels of adenosine in tumors are higher than in normal tissues due, at least in part, to hypoxia. Extracellular adenosine binds to A2AR and/or A2BR on the surface of anti-tumor effector cells and subsequently increases cAMP levels. To break this potentially immunosuppressive sequence, therapeutic targets will include the accumulation of extracellular adenosine, binding of adenosine to A2AR/A2BR and cellular expression of A2AR/A2BR. Inhibitor of ectonucleotidases (e.g. CD73) can diminish metabolic production of adenosine from adenosine phosphates. Antagonists of A2AR/A2BR can block interaction of adenosine with the cell surface receptors. In adoptive immunotherapy, anti-tumor effector cells may be pretreated to be insensitive to adenosine by elimination of the receptor expression with siRNA or by simply culturing the cells with adenosine receptor agonist. Such treatment is expected to abolish adenosine-mediated immunosuppression in tumor microenvironment and promote tumor eradication by immune cells.