2.Immune Checkpoint
The immune system consists of innate and acquired immunity, which, once activated, clears infectious pathogens and tumor cells. There are inhibitory pathways in antimicrobial or antitumor immune responses that normally maintain autotolerance to avoid excessive damage and limit associated tissue damage [17, 18]. These receptor and ligand inhibitory pathways are known as ”Immune Checkpoint” and are used by tumor cells to avoid Immune attack. The development of monoclonal antibodies to inhibit these checkpoints, thereby removing the Inhibition of immunocytes and enabling them to recognize and kill tumor cells, is called ”Immune Checkpoint Inhibition”. These drugs are called ”Immune Checkpoint Inhibitor” (ICI) [19, 20]. FDA-approved anti-CTLA-4 and anti-PD-1 antibodies for cancer treatment led to the belief that immunotherapy for cancer was realistic and further encouraged the development of other new ICIs [21-23]. Immunotherapy is becoming an important treatment for cancer patients [1, 12]. Immune checkpoint blocking (ICB) based on monoclonal antibody (mAb) has also proved to be a safe and effective treatment for hematologic malignancies in the past decade [18, 23]. In oncology, checkpoints currently targeted by inhibitors to amplify the reactivity of T cells, NK cells or bone marrow cells include CTLA-4[24],PD-1,PD-L1(PD1 ligand 1/CD274),LAG-3(CD223),TIM3(T cell immunoglobulin-3),TIGIT(T cell immunoglobulin and ITIM domain)[25],VISTA(V-domain immunoglobulin suppressor of T cell activation)[26],B7/H3(CD276),KIR (killer cell immunoglobulin-like receptors),NKG2A,A2AR,CD39,CD73,CSF1R,CD47,etc.[18, 27, 28].(Figure 2)
Each member of the adenosine signaling pathway constitutes a different drug target, meaning that it is possible for combined therapy with not just only one drug to target this or complementary signaling pathway[29]. Many of these combinations are currently in preclinical and clinical trials, such as anti-CD73 and anti-A2aR combinations, anti-CD73 and anti-PD-1 combinations, as well as anti-A2aR and anti-TIGIT antibody combinations [17, 27, 30-32].(table 1)