Abstract
The adenosine pathway plays a key role in modulating immune responses in physiological and pathological conditions. Physiologically, anti-inflammatory effects of adenosine balance pro-inflammatory adenosine 5’-triphosphate (ATP), protecting tissues from damage caused by activated immune cells. Pathologically, increased adenosine monophosphatase (AMPase) activity in tumors leads to increased adenosine production, generating a deeply immunosuppressed microenvironment and promoting cancer progression. Adenosine emerges as a promising target for cancer therapy. It mediates protumor activities by inducing tumor cell proliferation, angiogenesis, chemoresistance, and migration/invasion by tumor cells. It also inhibits the functions of immune cells, promoting the formation of a tumor-permissive immune microenvironment and favoriting tumor escape from the host immune system. Pharmacologic inhibitors, siRNA or antibodies specific for the components of the adenosine pathway, or antagonists of adenosine receptors have shown efficacy in pre-clinical studies in various in vitro and in vivo tumor models and are entering the clinical arena. Inhibition of the adenosine pathway alone or in combination with classic immunotherapies offers a potentially effective therapeutic strategy in cancer.
Highlights
The immune system plays an important role in the prevention as well as progression of malignancy [1]
We demonstrated in M1 macrophages that ATPase activity was decreased, while M2-type macrophages increased adenosine 5’-triphosphate (ATP)/ADP/adenosine monophosphate (AMP) hydrolysis through increased expression of CD39/CD73
We found that A2AR and P2X7R activation was necessary for IL-10, monocyte chemoattractant protein-1 (MCP-1), and IL-6 release by macrophages after interaction with glioblastoma
Summary
The immune system plays an important role in the prevention as well as progression of malignancy [1]. ADO acting directly on tumor cells promotes growth, survival, angiogenesis, chemoresistance, and metastasis [12,13]. Under physiological conditions, ADO acting as an immuno-regulatory molecule protects normal tissues from inflammatory damage while in pathological conditions, it can impair anti-tumor immunity [14]. ADO attenuates functions of protective immune cells, including T cells and natural killer (NK) cells. It enhances the suppressive functions of regulatory T cells (Tregs), macrophages, and myeloid-derived suppressor cells (MDSCs), inducing cancer progression [15,16,17,18]. We review approaches to blocking the adenosine pathway in cancer, removing the immune function brake and restoring the host’s ability to control tumor progression
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