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Thesis
PSGL-1 signaling in CD8⁺ T cells is a key driver of impaired anti-tumor immunity in cutaneous melanoma
Master of Science (M.S.), Drexel University
Apr 2026
DOI:
https://doi.org/10.17918/00011344
Abstract
Immune checkpoint blockade (ICB) revolutionized the treatment of advanced cutaneous melanoma. Nonetheless, only a subset of patients benefits from immunotherapy. ICB resistance remains a major challenge, necessitating novel approaches towards immune checkpoint targeting. P-Selectin Glycoprotein Ligand 1 (PSGL-1), a primary selectin ligand for leukocyte recruitment to inflammation sites, is highly expressed by most immune cells and represents a novel targetable immune checkpoint with high potential. Previous studies using PSGL-1 deletion or blockade strongly suggest a CD8⁺ T cell-intrinsic checkpoint function to promote enhanced melanoma tumor control. However, the contribution of PSGL-1 signaling on individual immune cell compartments and its impact on cutaneous melanoma tumor development and control remained unclear. Here, we focused on three critical immune cell compartments and hypothesized that cell-specific ablation of PSGL-1 signaling in either DCs, macrophages/neutrophils, or CD8⁺ T cells independently is sufficient to recapitulate the improved cutaneous melanoma tumor control observed in Selplg^[-/-] (PSGL-1-deficient) mouse models. Using the Cre-LoxP system, we generated mice harboring cell specific targeted deletion of PSGL-1 in each of these three immune compartments and challenged them with the poorly immunogenic YUMM1.5 melanoma cell line. Our results suggest that eliminating PSGL-1 signaling within DCs or macrophages/neutrophils does not play a significant role in promoting anti-tumor immune responses in our preclinical models. Conversely, CD8⁺ T cell-specific ablation of PSGL-1 signaling significantly improved tumor growth control and increased overall survival. Moreover, combination of CD8⁺ T cell-specific deletion of PSGL-1 with anti-PD-1 therapy synergistically improved tumor growth control, further corroborating the pivotal role of CD8⁺ T cells in the overall anti-tumor response against cutaneous melanoma. This synergistic effect underscores the non-redundant and parallel inhibitory function of PSGL-1 relative to PD-1 on CD8⁺ T cells, establishing it as a promising candidate target for next-generation ICB strategies.
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Details
- Title
- PSGL-1 signaling in CD8⁺ T cells is a key driver of impaired anti-tumor immunity in cutaneous melanoma
- Creators
- Mahary Lalarizo Rakoto
- Contributors
- Jennifer L. Hope (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University
- Number of pages
- ix, 70 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Medicine (Graduate); College of Medicine; Hematology and Oncology; Drexel University
- Other Identifier
- 991022176276104721