2. Academic Validation
  3. PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion

PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion

  • Cell Rep. 2023 May 30;42(5):112436. doi: 10.1016/j.celrep.2023.112436.
Jennifer L Hope 1,  Dennis C Otero 1,  Eun-Ah Bae 1,  Christopher J Stairiker 1,  Ashley B Palete 1,  Hannah A Faso 1,  Michelle Lin 1,  Monique L Henriquez 1,  Sreeja Roy 1,  Hyungseok Seo 2,  Xue Lei 3,  Eric S Wang 4,  Savio Chow 3,  Roberto Tinoco 1,  Gregory A Daniels 5,  Kevin Yip 3,  Alexandre Rosa Campos 6,  Jun Yin 7,  Peter D Adams 3,  Anjana Rao 2,  Linda M Bradley 8
Affiliations

Affiliations

  • 1 Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 2 Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  • 3 Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 4 Cancer Molecular Therapeutics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 5 Department of Medicine, Moores Cancer Center at UC San Diego Health, La Jolla, CA 92037, USA.
  • 6 Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 7 Bioinformatics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 8 Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: lbradley@sbpdiscovery.org.
PMID: 37115668 DOI: 10.1016/j.celrep.2023.112436
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.

Keywords

CD8 T cells; CP: Immunology; T cell exhaustion; T cell metabolism; T cell signaling; chronic infection; melanoma; tumor immunity.

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