The Hypoxia-adenosinergic Immunosuppression and Redirection of Immune Response in Tumor Microenvironment

Abstract

In this chapter, we will focus on physiological regulators of activated immune cells in cancerous tissue microenvironments. This consideration started when we were contemplating the molecular mechanism that would be responsible for the so-called Hellstrom Paradox. Indeed, it was not explained why cancer patients often have tumor-recognizing effector T cells without having tumor rejection. The latest great advances in identification of various immunological negative regulators of immune response still left room for tumor defense by physiological inhibitors of antitumor T and natural killer (NK) cells. We started by assuming that cancerous tissues could be misguidedly protected by the same mechanism, which saves lives by protecting vital tissues from collateral damage by overactive immune cells during the antipathogen immune response. In our search for a mechanism that protects tissues from collateral damage, we first focused on intracellular cyclic adenosine monophosphate (cAMP) which was long known to be immunosuppressive. It was important to identify which of the many Gs protein-coupled receptors is actually physiologically responsible for inhibition of immune response in tumor microenvironment. Levels of extracellular adenosine are high in inflamed and cancerous tissues corresponding to local hypoxia. A2A and A2B subtypes of adenosine receptor, which are coupled to cAMP-elevating Gs protein, are predominantly expressed in immune cells. Indeed, extracellular adenosine endogenously generated by degradation of adenosine triphosphate (ATP) could suppress immune response and immunoregulation by adenosine was notable in tumor microenvironment. Blockade of the hypoxia-adenosinergic immunosuppression may be a promising approach to eradicate cancer, especially when it is combined with adoptive immunotherapy or cancer vaccine.