Investigating PSGL-1’s role in regulating CD8+ T cell responses, Hope et al. showed that PSGL-1 co-ligated with the TCR to inhibit proximal TCR signaling via Zap70 to restrain mouse and human CD8+ T cell activation, driving terminal T cell exhaustion. In PSGL-1-deficient conditions compared to WT, CD8+ TILs responded better to low affinity TCR ligands, exhibited enhanced glycolysis, and increased numbers of stem cell-like progenitors with Teff function. Therapeutic PSGL-1 blockade decreased T cell exhaustion and inhibited growth of PD-1 blockade-resistant melanoma suggesting PSGL-1 could be targeted to treat PD-1-non-responsive tumors.
Contributed by Katherine Turner
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.
Author Info: (1) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Pro
Author Info: (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) 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. (3) 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. (4) 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. (5) 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. (6) 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. (7) 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. (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. (9) 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. (10) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA. (11) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (12) Cancer Molecular Therapeutics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (13) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (14) 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. (15) Department of Medicine, Moores Cancer Center at UC San Diego Health, La Jolla, CA 92037, USA. (16) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (17) Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (18) Bioinformatics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (19) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (20) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA. (21) 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.
