Fig 1.

Simplified illustration of the mechanism of checkpoint inhibitor modulation of the immune response to cancer cells. a) Normal physiological state. In the unaltered physiological state, detection of cancer cell antigens, either via antigen-presenting cells or cancer cells themselves, causes T-cell activation. Pictured are two physiological mechanisms that reduce exaggerated immune response, but also immunosurveillance and therefore elimination of cancer cells. (1) CTLA-4 outcompetes CD-28 to bind to CD-80. Instead of further activation by CD-28, CTLA-4 sends inhibitory signals to deactivate T-cells. (2) Binding of PD-L-1 on the cancer cell or antigen-presenting cell to PD-1 on a T-cell activates inhibitory signals to immune response and encourages apoptosis of immune cells. b) State with checkpoint inhibitor therapy. Checkpoint inhibitor therapy acts on both mechanisms via three targets. (1) Anti-CTLA-4 mAb binds to CTLA-4, resulting in subsequent promotion of T-cell activation and survival by the CD-28 pathway. (2) Anti-PD-1 mAb binds to PD-1 on T-cells, preventing a negative feedback pathway. (3) Anti-PD-L-1 mAb binds to PD-L-1 on cancer cells, preventing the same negative feedback. CTLA-4 = cytotoxic T-lymphocyte antigen 4; mAb = monoclonal antibody; PD-1 = protein death 1; PD-L-1 = protein death ligand 1.