Abstract
474 Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer
Journal for immunotherapy of cancer, v 13(Suppl 2), pp A539-A539
01 Nov 2025
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Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is an aggressive, poorly immunogenic cancer that is highly refractory to all currently available treatments including existing immune checkpoint blockade (ICB) therapies. Patient prognosis is poor with a 5-year overall survival rate of only 13%.1 2 As such, there is a critical need to develop novel therapeutic strategies to improve patient outcomes. P-selectin glycoprotein ligand 1 (PSGL-1) is an intrinsic regulator of CD8+ T cells that promotes the development of functional exhaustion and is highly expressed on tumor-infiltrating CD8+ T cells in treatment naïve PDAC patients.3 4 We hypothesized that PSGL-1-mediated immune suppression is a critical barrier to effective anti-tumor immunity in PDAC.MethodsPSGL-1 gene expression (SELPLG) and correlation with patient survival was evaluated in publicly available single-cell RNA-sequencing and TCGA datasets, respectively. Preclinical studies used orthotopic injection of KPC.4662 tumor cells in 6-8 week old C57BL/6 (wildtype control) and PSGL-1-/- mice. Immune cell infiltration and profiling was completed using flow cytometry and histology. Spatial proteomics was completed using the Akoya PhenoCycler.ResultsTumor burden in PSGL-1-/- mice was reduced by >50% compared to controls. Moreover, fewer mice developed tumor metastases in the intraperitoneal cavity, liver, and lungs. Total immune infiltration (CD45+) was markedly increased and significant increases in T cells and decreases in myeloid cells were found. Spatial proteomic analyses revealed significant remodeling of the PDAC tumor microenvironment in PSGL-1-/- mice. We observed a significant decrease in proliferating tumor cells and increase in the interactions of T cells with antigen-presenting cells in tumors from PSGL-1-/- mice. CD8+ T cells from PSGL-1-/- mice were less terminally differentiated and retained greater functionality. We show that tumor protection by PSGL-1-/- mice is T cell dependent, as transient depletion of T cells prior to tumor implantation ablated tumor control by PSGL-1-/- mice. Further, we observed that PD-1 ICB resulted in tumor eradication in 85% of PSGL-1-/- animals, demonstrating a profound synergistic effect of PD-1 inhibition in the absence of PSGL-1.ConclusionsIn the absence of PSGL-1, we observe significantly reduced growth of primary orthotopic PDAC tumors, decreased metastatic spread, and dramatic remodeling of the PDAC tumor microenvironment. Critically, deletion of PSGL-1 in immune cells promoted responsiveness to therapeutic PD-1 ICB and tumor clearance. Our data support that PSGL-1 is a critical, novel ICB target with high translational potential for promoting immune responses to PDAC tumors.AcknowledgementsThis research was supported in part by the Sanford Burnham Prebys NCI-Designated Cancer Center Support Grant, P30 CA030199 (Pilot Award: Bradley, Commisso); R01CA207189 (Commisso); R01CA254806 (Commisso); the Sidney Kimmel NCI-Designated Comprehensive Cancer Center (American Cancer Society Institutional Research Grant, (Hope); Goal Line Award, (Hope). In addition, we would like to acknowledge the contributions of the following Sanford Burnham Prebys Core facilities: the Flow Cytometry Core (RRID:SCR_014854; Yoav Altman, Benji Portillo), the Vivarium Core (Buddy Charbono and Andy Vasquez), and the Histology Core (Guillermina Garcia and Monica Sevilla). This work was supported by The NIH Shared Instrumentation Grant S10OD032325 for the Cytek Aurora housed in the Flow Cytometry Core at Sanford Burnham Prebys.ReferencesMorrison AH, Byrne KT, Vonderheide RH. Immunotherapy and prevention of pancreatic cancer. Trends Cancer. 2018 Jun;4(6):418-428.Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open. 2021 Apr 1;4(4):e214708.Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, Lin M, Henriquez ML, Roy S, Seo H, Lei X, Wang ES, Chow S, Tinoco R, Daniels GA, Yip K, Campos AR, Yin J, Adams PD, Rao A, Bradley LM. PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion. Cell Rep. 2023 May 30;42(5):112436.Tinoco RF, Carrette ML, Barraza DC, Otero J, Magana MW, Bosenberg SL Swain, Bradley LM. PSGL-1 is an immune checkpoint regulator that promotes t cell exhaustion. 2016;44:1190–1203.Ethics ApprovalThis study was carried out in accordance with the recommendations and approval of the Institutional Animal Care and Use Committee. Animal Subject Assurance Number: A3053-01
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Details
- Title
- 474 Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer
- Creators
- Linda Bradley - Discovery InstituteZhang YijuanHetrick Hannah AFEvelyn Sanchez-HernandezSilvestri BeatriceBrianna Smith - Sanford Burnham Prebys Medical Discovery InstituteNakil SanmatiRoy SreejaMichelle Lin - Discovery InstitutePalete AshleyMaganti SwethaLing LiDenis Otero - Discovery InstituteByrne KatelynGabriele Romano - Drexel UniversityWill Wang - Discovery InstituteJennifer Hope - Drexel UniversityCommisso Cosimo
- Publication Details
- Journal for immunotherapy of cancer, v 13(Suppl 2), pp A539-A539
- Publisher
- BMJ Publishing Group
- Resource Type
- Abstract
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Other Identifier
- 991022130764204721