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PSGL-1 directs early TCR signaling to repress metabolism and promote T cell exhaustion by modulating the TCF-1/TOX axis in CD8+ T cells
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PSGL-1 directs early TCR signaling to repress metabolism and promote T cell exhaustion by modulating the TCF-1/TOX axis in CD8+ T cells

Jennifer Hope, Dennis Otero, Eun-Ah Bae, Christopher Stairiker, Ashley Palete, Hannah Faso, Monique Henriquez, Hyungseok Seo, Xue Lei, Eric Wang, …
bioRxiv
27 Jan 2022
DOI: https://doi.org/10.1101/2022.01.24.477602
url
https://doi.org/10.1101/2022.01.24.477602View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Antitumor activity CD162 antigen CD8 antigen Chronic infection Glycolysis Hepatocyte nuclear factor 1 Immune checkpoint Immunotherapy Lymphocytes Lymphocytes T Melanoma Metabolism PD-1 protein PD-L1 protein Phenotypes T-cell receptor Therapeutic targets Tumors ZAP-70 protein
We previously identified the adhesion molecule PSGL-1 as a T cell intrinsic immune checkpoint regulator of T cell exhaustion. Here we show that the ability of PSGL-1 to restrain TCR sginaling correlates with decreased expression of the Zap70 inhibitor Ubash3b (Sts-1) in PSGL-1-deficient T cells. PSGL-1-deficency in T cells supports antitumor responses to a PD-1 blockade resistant melanoma wherein tumor-specific CD8+ T cells sustain an enhanced metabolic state, with an elevated metabolic gene signature that promotes increased glycolysis and glucose uptake to support effector functions. In models of chronic virus infection and cancer, this outcome was associated with CD8+ T cell stemness, as PSGL-1 deficient CD8+ T cells displayed increased TCF-1 and decreased TOX expression, a phenotype shown to be crucial for responsiveness to checkpoint inhibition. Further, we demonstrate that PSGL-1 signaling promotes development of exhaustion in human CD8+ T cells. Finally, pharmacologic blockade of PSGL-1 was sufficient to curtail T cell exhaustion and enhance functionality both with melanoma tumors and chronic LCMV infection, demonstrating that PSGL-1 represents a therapeutic target for immunotherapy for PD-1/PD-L1 resistant tumors. Competing Interest Statement The authors have declared no competing interest.

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