Targeting Hypoxia‐Adenosinergic Signaling to Enable Effective Anti‐Tumor Responses by Reprogramming the Immunosuppressive Tumor Microenvironment

Abstract

The hypoxia‐HIF‐1ɑ‐mediated generation of extracellular adenosine (eADO) and associated A2A adenosine receptor (A2AR) signaling represent a critical mechanism for resistance to anti‐tumor immune attack in an immunosuppressive tumor microenvironment (TME). This is supported by earlier clinical and preclinical findings that tumors exhibiting refractory responses to chemotherapeutic and immunotherapeutic interventions are often characterized by low tissue oxygen tension and elevation of intracellular cAMP triggered by the binding of adenosine to the A2AR. The ensuing signaling cascade results in the downregulation of T cell activation and increased production of anti‐inflammatory factors. Several classes of drugs have been proven in preclinical studies and clinical trials to weaken this powerful biochemical mechanism of immunosuppression and enable tumor rejection. Therapeutic approaches targeting the upstream and downstream stages of hypoxia‐adenosinergic negative immune regulation (i.e. A2AR antagonists, oxygenation, inhibition of adenosine generation or adenosine degradation) represent promising co‐adjuvants capable of inducing a more immunopermissive TME. The removal of this biochemical barrier may be the key to unleashing the full therapeutic potential of immunotherapies. For instance, the epithelial‐mesenchymal transition (EMT) program, which confers the ability of cancer cells to engage in metastatic dissemination, is associated with the acquisition of resistance to immune checkpoint blockade (ICB). Recent studies have demonstrated that abrogation of the adenosine‐generating ectoenzyme CD73 sensitizes mice bearing quasi‐mesenchymal (qM) tumors to anti‐CTLA4 ICB through an increase in CD8+ T cell infiltration and cytotoxicity. Furthermore, the present study demonstrates the differential expression of adenosinergic enzymes and EMT transcription factors (EMT‐TFs) in murine breast epithelial (E) and qM carcinoma cell lines cultured in normoxic (21% oxygen) and hypoxic (1% oxygen) conditions in vitro. As hypothesized, the stabilization of HIF‐1ɑ in hypoxic conditions resulted in the upregulation of some adenosine‐generating enzymes and changes in adenosine metabolism. These results elucidate an additional mechanism through which hypoxia can contribute to the assembly of an immunosuppressive TME, while highlighting the categorical differences between the E vs qM states of carcinoma cells.