Lerrer et al. showed that unlike naive cells, TCM and TEM cells proliferated more when stimulated through TCR and PD-1 than through only TCR. PD-1 signaling regulated more than half of the TCR transcriptome to fine tune the response, and PD-L2 had more of an impact than PD-L1. Also, PD-1 ligation induced (or inhibited) genes independent of TCR signaling and differentially in T cell functional subsets; PD-L1 was more impactful. PD-L1 or PD-L2 treatment boosted TCR-induced STAT1 and STAT2 levels. Lower STAT1 and/or STAT2 T cell expression levels were associated with better checkpoint blockade response and overall survival in patients.
Contributed by Paula Hochman
ABSTRACT: Despite the obvious inhibitory outcome of PD-1 signaling, an additional series of functions are activated. We have observed that T cells stimulated through the T cell receptor (TCR) and PD-1 primarily do not proliferate; however, there is a population of cells that proliferates more than through TCR stimulation alone. In this study, we performed flow cytometry and RNA sequencing on individual populations of T cells and discovered that unlike naive T cells, which were inhibited following PD-1 ligation, T cells that proliferated more following PD-1 ligation were associated with effector and central memory phenotypes. We showed that these populations had different gene expression profiles following PD-1 ligation with PD-L1 compared to PD-L2. The presence of transcriptionally and functionally distinct T cell populations responsive to PD-1 ligation provides new insights into the biology of PD-1 and suggest the use of T cell subset-specific approaches to improve the clinical outcome of PD-1 blockade.