Investigating PSGL-1’s role in regulating CD8+ T cell responses, Hope et al. showed that PSGL-1 co-ligated with the TCR to inhibit proximal TCR signaling via Zap70 to restrain mouse and human CD8+ T cell activation, driving terminal T cell exhaustion. In PSGL-1-deficient conditions compared to WT, CD8+ TILs responded better to low affinity TCR ligands, exhibited enhanced glycolysis, and increased numbers of stem cell-like progenitors with Teff function. Therapeutic PSGL-1 blockade decreased T cell exhaustion and inhibited growth of PD-1 blockade-resistant melanoma suggesting PSGL-1 could be targeted to treat PD-1-non-responsive tumors.
Contributed by Katherine Turner
ABSTRACT: PSGL-1 (P-selectin glycoprotein-1) is a T cell-intrinsic checkpoint regulator of exhaustion with an unknown mechanism of action. Here, we show that PSGL-1 acts upstream of PD-1 and requires co-ligation with the T cell receptor (TCR) to attenuate activation of mouse and human CD8(+) T cells and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. PSGL-1 deficiency empowers CD8(+) T cells to respond to low-affinity TCR ligands and inhibit growth of PD-1-blockade-resistant melanoma by enabling tumor-infiltrating T cells to sustain an elevated metabolic gene signature supportive of increased glycolysis and glucose uptake to promote effector function. This outcome is coupled to an increased abundance of CD8(+) T cell stem cell-like progenitors that maintain effector functions. Additionally, pharmacologic blockade of PSGL-1 curtails T cell exhaustion, indicating that PSGL-1 represents an immunotherapeutic target for PD-1-blockade-resistant tumors.