Definition

An orally bioavailable prodrug and selective antagonist of the immunomodulatory checkpoint molecule adenosine A2B receptor (A2BR; ADORA2B), with potential anti-inflammatory, immunomodulating and antineoplastic activities. Upon oral administration, A2BR antagonist TT-702 is converted to its active metabolite TT-478. TT-478 selectively binds to and blocks A2BR expressed on various cancer cell types and numerous immune cells, such as dendritic cells (DCs), mast cells, macrophages and lymphocytes. This prevents the binding of adenosine to A2BR, inhibits A2BR activity and prevents adenosine/A2BR-mediated signaling. This abrogates adenosine/A2BR-mediated immunosuppression, activates immune stimulatory cell, such as DCs and cytotoxic T lymphocytes (CTLs), and reduces immunosuppressive cells myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs). This suppresses cancer cell growth, which leads to an inhibition of cell proliferation and metastasis. A2BR inhibition also prevents the release of various growth factors, cytokines and chemokines, which may further abrogate the adenosine-mediated immunosuppression in the tumor microenvironment (TME). This further activates the immune system to exert anti-tumor immune responses against tumor cells leading to tumor cell killing. In addition, under non-cancerous inflammatory conditions, inhibition of A2BR leads to reduced activation and proliferation of various immune cells, which results in decreased pro-inflammatory cytokine production and may prevent inflammation. A2BR, a G protein-coupled signaling receptor, is expressed on the cell surfaces of numerous immune cells and is often overexpressed on a variety of cancer cell types, especially under hypoxic conditions; it plays a key role in their proliferation, progression and metastasis. Adenosine is overproduced under inflammatory conditions and plays a key role in pro-inflammatory actions. Adenosine is often overproduced by tumor cells and plays a key role in immunosuppression and tumor cell proliferation. The pro- and anti-inflammatory effects of adenosine and A2BR are cell type-specific and dependent on the extracellular microenvironment.