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
  • 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: [email protected].
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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