1. PSGL-1 attenuates early TCR signaling to suppress CD8 + T cell progenitor differentiation and elicit terminal CD8 + T cell exhaustion.
- Author
-
Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, Lin M, Henriquez ML, Roy S, Seo H, Lei X, Wang ES, Chow S, Tinoco R, Daniels GA, Yip K, Campos AR, Yin J, Adams PD, Rao A, and Bradley LM
- Subjects
- Humans, Cell Differentiation, Receptors, Antigen, T-Cell metabolism, T-Cell Exhaustion, CD8-Positive T-Lymphocytes metabolism, Programmed Cell Death 1 Receptor metabolism
- 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., Competing Interests: Declaration of interests L.M.B. and R.T. hold patents for PSGL-1 modulators and uses thereof (US10858436B2, WO2016007653A3). L.M.B. and J.L.H. hold patents for PSGL-1 antagonists and uses thereof (63/481570)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF