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Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer
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Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer

Jennifer L. Hope, Yijuan Zhang, Hannah A. F. Hetrick, Evelyn S. Sanchez-Hernandez, Beatrice Silvestri, Brianna J. Smith, Sanmati H. Nakil, Sreeja Roy, Michelle Lin, Ashley B. Palete, …
bioRxiv
27 May 2025
DOI: https://doi.org/10.1101/2025.05.22.655365
PMID: 40501664
url
https://www.biorxiv.org/content/biorxiv/early/2025/05/27/2025.05.22.655365.full.pdfView
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Abstract

Immunology
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer for which there is a critical need to identify novel therapeutic targets. Herein we define PSGL-1 as a checkpoint inhibitor using a syngeneic orthotopic model of PDAC. As with PDAC patients, CD8+ T cells within murine PDAC tumors expressed high levels of PSGL-1. PSGL-1-/- mice displayed striking T cell-dependent control of primary tumors and lung metastases. Extensive spatial remodeling within PDAC tumors occurred in PSGL-1-/- mice with a dramatic loss of proliferating tumor cells and an increase in CD8+ T cell engagement of antigen-presenting cells. The prominent CD8+ T cell infiltrates included subsets of pre-exhausted T cells retaining hallmarks of stemness and multifunctional effector capacity. These changes enabled a near complete response of PDAC to therapeutic PD-1 blockade. Our findings identify PSGL-1 as a key regulator of anti-tumor immunity in PDAC, highlighting its potential as a therapeutic target to limit CD8+ T cell exhaustion and enhance immunotherapy response. Hope et al describe a pivotal function of PSGL-1 in CD8+ T cell responses to pancreatic ductal adenocarcinoma. Genetic deletion of PSGL-1 elicits tumor control by increasing T cell infiltration and maintaining functional subsets, thereby promoting sensitivity to PD-1 blockade.

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