Cell Reports (May 2023)
PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion
- Jennifer L. Hope,
- Dennis C. Otero,
- Eun-Ah Bae,
- Christopher J. Stairiker,
- Ashley B. Palete,
- Hannah A. Faso,
- Michelle Lin,
- Monique L. Henriquez,
- Sreeja Roy,
- Hyungseok Seo,
- Xue Lei,
- Eric S. Wang,
- Savio Chow,
- Roberto Tinoco,
- Gregory A. Daniels,
- Kevin Yip,
- Alexandre Rosa Campos,
- Jun Yin,
- Peter D. Adams,
- Anjana Rao,
- Linda M. Bradley
Affiliations
- Jennifer L. Hope
- 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
- Dennis C. Otero
- 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
- Eun-Ah Bae
- 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
- Christopher J. Stairiker
- 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
- Ashley B. Palete
- 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
- Hannah A. Faso
- 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
- Michelle Lin
- 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
- Monique L. Henriquez
- 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
- Sreeja Roy
- 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
- Hyungseok Seo
- Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Xue Lei
- Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Eric S. Wang
- Cancer Molecular Therapeutics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Savio Chow
- Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Roberto Tinoco
- 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
- Gregory A. Daniels
- Department of Medicine, Moores Cancer Center at UC San Diego Health, La Jolla, CA 92037, USA
- Kevin Yip
- Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Alexandre Rosa Campos
- Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Jun Yin
- Bioinformatics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Peter D. Adams
- Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Anjana Rao
- Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Linda M. Bradley
- 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; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 5
p. 112436
Abstract
Summary: 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.
