T-cell-intrinsic and -extrinsic regulation of PD-1 function.

Cancer immunotherapies that target PD-1 (programmed cell death 1) aim to destroy tumors by activating tumor-specific T cells that are otherwise inactivated by PD-1. Although these therapies have significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment, only a limited proportion of patients benefits from the therapies currently. Therefore, there is a continued need to decipher the complex biology of PD-1 to improve therapeutic efficacies as well as to prevent immune-related adverse events. Especially, the spaciotemporal context in which PD-1 functions and the properties of T cells that are restrained by PD-1 are only vaguely understood. We have recently revealed that PD-1 function is strictly restricted at the activation phase of T-cell responses by the cis-interactions of PD-L1 and CD80 on antigen-presenting cells, which is critical for the induction of optimal T-cell responses. We also found that the sensitivity to the effects of PD-1 in T cells is essentially determined by T-cell-intrinsic factors. In T cells bearing T-cell antigen-receptors (TCRs) with lower affinity to antigenic peptides, PD-1 inhibits the expression of TCR-inducible genes more efficiently; thereby PD-1 preferentially suppresses low-affinity T cells. Thus, PD-1 function is coordinately regulated by various T-cell-intrinsic and -extrinsic factors that alter the responsiveness of T cells and the availability of PD-1 ligands. Precise and deeper understanding of the regulatory mechanisms of PD-1 is expected to facilitate the rational development of effective and safe immunotherapies.