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Updated: Jun 13, 2025
Immunophenotyping of Orthotopic Homograft Syngeneic of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry
Published on: October 9, 2018
Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer
Abstract:
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.
Summary:
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.
Insights
P-selectin glycoprotein ligand-1 (PSGL-1) acts as a checkpoint in pancreatic cancer. Removing PSGL-1 enhances CD8+ T cell activity, controlling tumor growth and improving immunotherapy response in pancreatic ductal adenocarcinoma.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited therapeutic options.
- There is a critical need for novel therapeutic targets to improve treatment efficacy in PDAC.
Purpose of the Study:
- To investigate the role of P-selectin glycoprotein ligand-1 (PSGL-1) as a potential therapeutic target in pancreatic ductal adenocarcinoma.
- To determine if targeting PSGL-1 can enhance anti-tumor immunity and improve response to immunotherapy.
Main Methods:
- Utilized a syngeneic orthotopic model of PDAC in mice.
- Generated PSGL-1 knockout (PSGL-1-/-) mice to assess the impact of PSGL-1 deletion on tumor growth and immune responses.
- Analyzed T cell infiltration, phenotype, and function within tumors.
- Evaluated the response to PD-1 blockade in the context of PSGL-1 deficiency.
Main Results:
- PSGL-1-/- mice showed significant T cell-dependent control of primary PDAC tumors and lung metastases.
- Tumors in PSGL-1-/- mice exhibited spatial remodeling, reduced proliferation, and increased CD8+ T cell engagement with antigen-presenting cells.
- Prominent CD8+ T cell infiltrates in PSGL-1-/- mice included stem-like, multifunctional effector subsets.
- PSGL-1 deficiency led to a near complete response to therapeutic PD-1 blockade.
Conclusions:
- PSGL-1 acts as a key regulator of anti-tumor immunity in pancreatic ductal adenocarcinoma.
- Targeting PSGL-1 can limit CD8+ T cell exhaustion and enhance the efficacy of immunotherapy, such as PD-1 blockade.
