5.Association of A2AR with other immune checkpoints
A2a receptor (A2aR) in the pathway of adenosinergic axis is becoming an important immune checkpoint. Adenosine levels in the extracellular fluid are upgraded in the TME due to the special metabolism of tumor cells, which contributes to tumor immune escape. Therefore, inhibitors of A2aR are being sought to enhance the effect of immunotherapy[2, 12].Several A2aR antagonists have been developed at present and have been tested in multiple preclinical studies. At least four drugs are currently in phase I clinical trials: CPI-444[9] (Corvus), PBF-509 (Novartis/Pablobiofarma), MK-3814 (Merck), AZD4635 (AstraZeneca/Heptares)[12].CPI-444 has been reported to intensify antineoplastic immunity and enhanced anti-PD-L1 mAb activity in mice. CPI-444 has also been exhibited to intensify the antitumor effect of adoptive metastases of HER2-specific CD8+T cells in tumor-bearing mice treated with cyclophosphamide and a novel gene-expressed whole cell vaccine (GVAX)[9]. Vipatant (REDOX /Juno therapy) and Etradine (Kyowa Hakko Kirin) are other kinds of promised oral A2a antagonists that have previously had an exam in clinical trials in Parkinson’s disease and may be effective in cancer patients. Recent research shows that A2aR restrains T cell proliferation and cytokine secretion and increases expression of PD-1 and CTLA-4 on surface[68, 69].Currently, the combination therapy of A2aR and other immune checkpoints is also attracting attention[9, 12].