Manipulating the PD-1 pathway to improve immunity

• Blocking PD-1 signaling rescues exhausted T cells in chronic infections and cancer.
• PD-1 pathway blockade unleashes effector T cell functions on target cells.
• Combining PD-1 pathway blockade to therapeutic vaccination improves T cell rescue.
• PD-1 pathway may regulate humoral immunity, but mechanisms are not well established.
• Further studies on how PD-1 modulates initiation of immune responses are needed.

PD-1 is an inhibitory receptor induced in T cells by antigen stimulation and sustained PD-1 expression plays a key role in T cell dysfunction. Blocking PD-1 signaling rescues exhausted T cells and is an effective treatment for chronic infections and cancer. Nonetheless, combining PD-1 pathway blockade to therapeutic vaccination should further improve T cell rescue. PD-1 is induced shortly after T cell priming, but little is known about the role of PD-1 in the initiation of immune responses. In addition, the PD-1 pathway may also modulate humoral responses, since both B cells and Tfh cells express PD-1. Therefore, even though much progress has been achieved by manipulation of the PD-1 pathway to rescue exhausted T cells, this powerful immunotherapy could still be further exploited.