Article
作者: Lei, Xue ; Stairiker, Christopher J. ; Wang, Eric S. ; Tinoco, Roberto ; Henriquez, Monique L. ; Yip, Kevin ; Hope, Jennifer L. ; Bradley, Linda M. ; Chow, Savio ; Seo, Hyungseok ; Lin, Michelle ; Yin, Jun ; Campos, Alexandre Rosa ; Otero, Dennis C. ; Palete, Ashley B. ; Bae, Eun-Ah ; Rao, Anjana ; Roy, Sreeja ; Daniels, Gregory A. ; Adams, Peter D. ; Faso, Hannah A.
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.