Abstract
Rewiring CD8+ T cell responses to PD-1 immune checkpoint blockade in pancreatic cancer via the inhibitory receptor PSGL-1 2680
The Journal of immunology (1950), v 214(Supplement_1), vkaf283570
01 Nov 2025
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Abstract
Abstract Description
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, poorly immunogenic cancer non-responsive to currently available treatments, including immune checkpoint blockade (ICB). P-selectin glycoprotein ligand 1 (PSGL-1) is an intrinsic regulator of CD8+ T cells that promotes the development of functional exhaustion and highly expressed on tumor-infiltrating CD8+ T cells in treatment naïve PDAC patients. We hypothesized that PSGL-1-mediated immune suppression is a critical barrier to effective anti-tumor immunity in PDAC. Using preclinical models of PDAC, we evaluated anti-tumor immunity in C57BL/6 control mice compared to PSGL-1KO mice. Tumor burden in PSGL-1KO mice was reduced by > 50% compared to controls and protected against metastatic disease. In addition to increased total immune infiltration (CD45+), CD8+ T cells from PSGL-1KO mice were less terminally differentiated and retained greater functionality. Our studies find that protection by PSGL-1KO mice is T cell dependent, as transient depletion of T cells prior to tumor implantation ablated tumor control by PSGL-1KO mice. Further, we observed that PD-1 ICB resulted in tumor ablation in 85% of PSGL-1KO animals, demonstrating a profound synergistic effect of PD-1 inhibition in the absence of PSGL-1. Our data support that PSGL-1 is a critical novel ICB target with high translational potential for promoting immune responses to PDAC tumors.
Funding Sources
NIH/NCI P30CA030199 Pilot; NIH/NCI R01CA254806
Topic Categories
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Metrics
5 Record Views
Details
- Title
- Rewiring CD8+ T cell responses to PD-1 immune checkpoint blockade in pancreatic cancer via the inhibitory receptor PSGL-1 2680
- Creators
- Jennifer L. HopeYijuan ZhangHannah Hetrick - Sanford Burnham Prebys Medical Discovery InstituteEvelyn Stefany Sanchez HernandezBeatrice Silvestri - Sanford Burnham Prebys Medical Discovery InstituteBrianna Smith - Sanford Burnham Prebys Medical Discovery InstituteSanmati Nakil - Sanford Burnham Prebys Medical Discovery InstituteSreeja Roy - Discovery InstituteMichelle Lin - Sanford Burnham Prebys Medical Discovery InstituteAshley Palete - Sanford Burnham Prebys Medical Discovery InstituteSwetha Maganti - Sanford Burnham Prebys Medical Discovery InstituteLily Lang - Sanford Burnham Prebys Medical Discovery InstituteDennis C. Otero - Sanford Burnham Prebys Medical Discovery InstituteKatelyn Byrne - Oregon Health & Science UniversityGabriele RomanoYu Xin (Will) Wang - Sanford Burnham Prebys Medical Discovery InstituteCosimo Commisso - Sanford Burnham Prebys Medical Discovery InstituteLinda M. Bradley - Discovery Institute
- Publication Details
- The Journal of immunology (1950), v 214(Supplement_1), vkaf283570
- Publisher
- Oxford University Press
- Number of pages
- 1
- Grant note
- NIH/NCI: P30CA030199, R01CA254806
NIH/NCI P30CA030199 Pilot; NIH/NCI R01CA254806
- Resource Type
- Abstract
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Web of Science ID
- WOS:001627327100001
- Other Identifier
- 991022135403604721