P-selectin glycoprotein ligand 1 promotes T cell lymphoma development and dissemination

Pereira, João L.; Cavaco, P; Silva, Ricardo C. da; Pacheco-Leyva, Ivette; Mereiter, Stefan; Pinto, Roberto; Reis, Celso A.; Santos, Nuno

doi:10.1016/j.tranon.2021.101125

Cited by 7 publications

(8 citation statements)

References 40 publications

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“…20 Earlier research revealed that PSGL-1 promoted tumor growth and dissemination in mouse models of lymphoma and multiple myeloma. 36,39,40 The finding that PSGL-1 antibodies trigger malignant lymphoid cell death indicates that the selective advantage of PSGL-1 expression for lymphoma or leukemia development may render malignant cells vulnerable for targeted immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Antibody targeting of surface P‐selectin glycoprotein ligand 1 leads to lymphoma apoptosis and tumorigenesis inhibition

Pereira,

Ferreira,

dos Santos

2024

Hematological Oncology

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Lymphomas are a heterogeneous group of diseases that originate from T, B or natural killer cells. Lymphoma treatment is based on chemotherapy, radiotherapy, and monoclonal antibody (mAb) or other immunotherapies. The P‐selectin glycoprotein ligand 1 (PSGL‐1) is expressed at the surface of hematological malignant cells and has been shown to have a pro‐oncogenic role in multiple myeloma and lymphoma. Here, we investigated the expression and therapeutic potential of PSGL‐1 in T and B cell lymphomas. By flow cytometry analysis, we found that PSGL‐1 was expressed in both T and B cell‐derived lymphoma cell lines but generally at higher levels in T cell lymphoma cell lines. For most T and B cell‐derived lymphoma cell lines, in vitro targeting with the PL1 mAb, which recognizes the PSGL‐1 N‐terminal extracellular region and blocks functional interactions with selectins, resulted in reduced cell viability. The PL1 mAb pro‐apoptotic activity was shown to be dose‐dependent, to be linked to increased ERK kinase phosphorylation, and to be dependent on the MAP kinase signaling pathway. Importantly, anti‐PSGL‐1 treatment of mice xenografted with the HUT‐78 cutaneous T‐cell lymphoma cell line resulted in decreased tumor growth, had no effect on in vivo proliferation, but increased the levels of apoptosis in tumors. Anti‐PSGL‐1 treatment of mice xenografted with a Burkitt lymphoma cell line that was resistant to anti‐PSGL‐1 treatment in vitro, had no impact on tumorigenesis. These findings show that PSGL‐1 antibody targeting triggers lymphoma cell apoptosis and substantiates PSGL‐1 as a potential target for lymphoma therapy.

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Section: Discussionmentioning

confidence: 99%

Antibody targeting of surface P‐selectin glycoprotein ligand 1 leads to lymphoma apoptosis and tumorigenesis inhibition

Pereira,

Ferreira,

dos Santos

2024

Hematological Oncology

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“…20 Finally, in lymphoma mouse models PSGL-1 expression was found to promote lymphoma development and dissemination to distant organs. 39,40 Taking into consideration these findings, we sought to assess whether PSGL-1 could be a therapeutic target in lymphoma. Here, we report PSGL-1 expression at the surface of several human lymphoma cell lines.…”

Section: Introductionmentioning

confidence: 99%

Antibody targeting of surface PSGL-1 glycoprotein leads to lymphoma apoptosis and tumorigenesis inhibition

Pereira,

Ferreira,

dos Santos

2024

Preprint

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Lymphomas are a heterogeneous group of diseases that originate from T, B or natural killer (NK) cells. Lymphoma treatment is based on chemotherapy, radiotherapy, and monoclonal antibody (mAb) or other immunotherapies. The P-selectin glycoprotein ligand 1 (PSGL-1) is expressed at the surface of hematological malignant cells and has been shown to have a pro-oncogenic role in multiple myeloma and lymphoma. Here, we investigated the expression and therapeutic potential of PSGL-1 in T and B cell lymphomas. By flow cytometry analysis, we found that PSGL-1 was expressed in both T and B cell-derived lymphoma cell lines but generally at higher levels in T cell lymphoma cell lines. For most T and B cell-derived lymphoma cell lines, in vitro targeting with the PL1 mAb, which recognizes the PSGL-1 N-terminal extracellular region and blocks functional interactions with selectins, resulted in reduced cell viability. The PL1 mAb pro-apoptotic activity was shown to be dose-dependent, to be linked to increased ERK kinase phosphorylation, and to be dependent on the MAP kinase signaling pathway. Importantly, anti-PSGL-1 treatment of mice xenografted with the HUT-78 cutaneous T-cell lymphoma (CTCL) cell line resulted in decreased tumor growth, had no effect on in vivo proliferation, but increased the levels of apoptosis in tumors. Anti-PSGL-1 treatment of mice xenografted with a Burkitt lymphoma (BL) cell line that was resistant to anti-PSGL-1 treatment in vitro, had no impact on tumorigenesis. These findings show that PSGL-1 antibody targeting triggers lymphoma cell apoptosis and substantiates PSGL-1 as a potential target for lymphoma therapy.

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“… 11 − 13 Cell surface glycoproteins such as CD44 and PSGL-1 interact with receptors expressed on endothelial cells, E- and P-selectins, and integrins. 7 , 14 − 21 This selectin–ligand interaction promotes the transient formation of membrane tethers and slings by HSPCs, resulting in their rolling along the endothelium at a shear stress of several dynes cm –2 generated by the blood flow. 2 , 3 , 22 …”

Section: Introductionmentioning

confidence: 99%

“…Hematopoiesis is the process of blood cellular component formation. It occurs during embryonic development and continues throughout adulthood to produce and replenish the blood system. − Hematopoietic stem-cell delivery to specific sites in the body is central to many physiological functions from immunity to cancer metastasis. , During the process of “homing”, HSPCs extravasate through the endothelial cells from peripheral blood to the bone marrow and start repopulating it by producing hematopoietic lineage cells including red blood cells, white blood cells, platelets, granulocytes, and erythrocytes. − The process of homing is initiated by tethering and rolling of the cells in flow followed by firm adhesion and transmigration into the tissue. , This is achieved by the cell’s interactions with the surface of the endothelium under the presence of external shear forces. − Cell surface glycoproteins such as CD44 and PSGL-1 interact with receptors expressed on endothelial cells, E- and P-selectins, and integrins. ,− This selectin–ligand interaction promotes the transient formation of membrane tethers and slings by HSPCs, resulting in their rolling along the endothelium at a shear stress of several dynes cm –2 generated by the blood flow. ,, …”

Section: Introductionmentioning

confidence: 99%

Nanoscopic Characterization of Cell Migration under Flow Using Optical and Electron Microscopy

et al. 2023

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Hematopoietic stem/progenitor cell (HSPC) and leukemic cell homing is an important biological phenomenon that takes place through essential interactions with adhesion molecules on an endothelial cell layer. The homing process of HSPCs begins with the tethering and rolling of the cells on the endothelial layer, which is achieved by the interaction between selectins on the endothelium to the ligands on HSPC/leukemic cells under shear stress of the blood flow. Although many studies have been based on in vitro conditions of the cells rolling over recombinant proteins, significant challenges remain when imaging HSPC/ leukemic cells on the endothelium, a necessity when considering characterizing cell-to-cell interaction and rolling dynamics during cell migration. Here, we report a new methodology that enables imaging of stem-cell-intrinsic spatiotemporal details during its migration on an endothelium-like cell monolayer. We developed optimized protocols that preserve transiently appearing structures on HSPCs/leukemic cells during its rolling under shear stress for fluorescence and scanning electron microscopy characterization. Our new experimental platform is closer to in vivo conditions and will contribute to indepth understanding of stem-cell behavior during its migration and cell-to-cell interaction during the process of homing.

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P-selectin glycoprotein ligand 1 promotes T cell lymphoma development and dissemination

Cited by 7 publications

References 40 publications

Antibody targeting of surface P‐selectin glycoprotein ligand 1 leads to lymphoma apoptosis and tumorigenesis inhibition

Antibody targeting of surface P‐selectin glycoprotein ligand 1 leads to lymphoma apoptosis and tumorigenesis inhibition

Antibody targeting of surface PSGL-1 glycoprotein leads to lymphoma apoptosis and tumorigenesis inhibition

Nanoscopic Characterization of Cell Migration under Flow Using Optical and Electron Microscopy

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