Targeting Hypoxia-A2A Adenosinergic Immunosuppression of Antitumor T Cells During Cancer Immunotherapy

Abstract

The blockade of immunological negative regulators offered a novel therapeutic approach that revolutionized the immunotherapy of cancer. Still, a significant portion of patients fail to respond to anti-PD-1/PD-L1 and/or anti-CTLA-4 therapy or experience significant adverse effects. We propose that one of the major reasons that many patients do not respond to this form of therapy is due to the powerful physiological suppression mediated by hypoxia-adenosinergic signaling. Indeed, both inflamed and cancerous tissues are hypoxic and rich in extracellular adenosine, in part due to stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). Adenosine signals through adenosine A2A receptors (A2AR) to suppress anti-tumor and anti-pathogen immune responses. Several classes of anti-hypoxia-A2AR therapeutics have been offered to refractory cancer patients, with A2AR blockers, inhibitors of adenosine-generating enzymes such as CD39 and CD73, and hypoxia-targeting drugs now reaching the clinical stage. Clinical results have confirmed preclinical observations that blockade of the hypoxia-adenosine-A2AR axis synergizes with inhibitors of immune checkpoints to induce tumor rejection. Thus, A2AR blockers provide a new hope for the majority of patients who are nonresponsive to current immunotherapeutic approaches including checkpoint blockade. Here, we discuss the discoveries that firmly implicate the A2AR as a critical and non-redundant biochemical negative regulator of the immune response and highlight the importance of targeting the hypoxia-adenosine-A2AR axis to manipulate anti-pathogen and anti-tumor immune responses.

Hyperhomocysteinemia and Cardiovascular Disease: Is the Adenosinergic System the Missing Link?

“…Neutrophil A 2A R inhibited inflammation in a rat model of meningitis and the oxidative activity of human neutrophils via the AMP/PKA cyclic pathway [ 166 , 167 ]. A 2A R are negative immune regulators that may be used to manipulate T cells, particularly during anti-tumor immune responses [ 168 ].…”

Immunosuppression in Gliomas via PD-1/PD-L1 Axis and Adenosine Pathway

“…Various clinical trials that evaluate purinergic modulation therapy along with anti-PD-1 mAb or anti-PD-L1 mAb are currently active or in the recruitment phase for multiple cancer types ( Supplementary Table S1 ). In fact, simultaneous therapy using PD-1 inhibitors and targeting the adenosine pathway was more effective in improving survival, reducing tumor growth, and limiting metastasis than single therapy in some types of cancer ( 106 – 108 ). Furthermore, there is a rising range of anti-CD73 mAbs being tested in combination with other immunotherapies, generating encouraging results ( 100 , 101 , 109 ).…”

Metabolic regulation in the immune response to cancer

“…The levels of extracellular nucleotides can be regulated by hypoxia. Specifically, the expression of CD39 and CD73 can be elevated by hypoxia through a HIF‐1‐dependent pathway [ 157 ]. Hypoxia also inhibits the expression of equilibrative nucleoside transporters (ENTs), which reduces the uptake of adenosine and thereby increases the level of extracellular adenosine [ 158 ].…”

“…Recent evidence showed that lncRNA calcium‐dependent kinase activation activated the nuclear factor kappa‐B (NF‐κB) pathway and induced tumor microenvironment remodeling under hypoxic tumor conditions [175, 176]. In addition, HIF‐1 increases extracellular adenosine production and accumulation by inducing CD39 and CD73 [ 157 ] and inhibiting ENT [ 158 ]. HIF‐1 also promotes tumor progression via other pathways, including cell immortalization, stem cell maintenance, genetic instability, and chemotherapy resistance, by directly or indirectly regulating the transcription of multiple target genes [ 177 ].…”