Costimulation, a surprising connection for immunotherapy

T cell cosignaling molecules may determine sensitivity to immunotherapy Checkpoint blockade is a type of immunotherapy that has shown unprecedented success in treating many cancers (1), particularly blockade of the T cell checkpoint protein called programmed cell death–1 (PD-1). This has created a unique situation in which clinical studies have outpaced efforts at the bench. As such, reliable predictive biomarkers have not yet been identified that define who will benefit from this method of treatment, and there is only a partial understanding of the mechanisms of sensitivity or resistance to immunotherapy. On pages 1428 and 1423 of this issue, Hui et al. (2) and Kamphorst et al. (3), respectively, elucidate important mechanisms of checkpoint blockade by demonstrating that PD-1 exerts its primary effect of dampening T cell activation by regulating a T cell receptor costimulatory molecule called cluster of differentiation 28 (CD28).