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Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity

SIMPLE SUMMARY: Platelet cloaking of tumor cells has been shown to play an important role in tumor metastasis and immune evasion. Multiple myeloma is a tumor of the plasma cells that colonizes different sites of the axial skeleton, including the skull. Herein, we show that specific carbohydrate stru...

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Autores principales: Natoni, Alessandro, Cerreto, Marina, De Propris, Maria Stefania, Petrucci, Maria Teresa, Fazio, Francesca, Intoppa, Stefania, Milani, Maria Laura, Kirkham-McCarthy, Lucy, Henderson, Robert, Swan, Dawn, Guarini, Anna, O’Dwyer, Michael, Foà, Robin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093642/
https://www.ncbi.nlm.nih.gov/pubmed/37046814
http://dx.doi.org/10.3390/cancers15072154
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author Natoni, Alessandro
Cerreto, Marina
De Propris, Maria Stefania
Petrucci, Maria Teresa
Fazio, Francesca
Intoppa, Stefania
Milani, Maria Laura
Kirkham-McCarthy, Lucy
Henderson, Robert
Swan, Dawn
Guarini, Anna
O’Dwyer, Michael
Foà, Robin
author_facet Natoni, Alessandro
Cerreto, Marina
De Propris, Maria Stefania
Petrucci, Maria Teresa
Fazio, Francesca
Intoppa, Stefania
Milani, Maria Laura
Kirkham-McCarthy, Lucy
Henderson, Robert
Swan, Dawn
Guarini, Anna
O’Dwyer, Michael
Foà, Robin
author_sort Natoni, Alessandro
collection PubMed
description SIMPLE SUMMARY: Platelet cloaking of tumor cells has been shown to play an important role in tumor metastasis and immune evasion. Multiple myeloma is a tumor of the plasma cells that colonizes different sites of the axial skeleton, including the skull. Herein, we show that specific carbohydrate structures present on the surface of multiple myeloma cells are essential in mediating direct interaction between the platelets and malignant plasma cells, which can be blocked by targeting P-selectin. Platelet binding to myeloma cells inhibits natural killer cell-mediated cytotoxicity, facilitating tumor immune evasion. We propose that platelets are important players in multiple myeloma dissemination, and targeting myeloma–platelet interactions may represent a novel strategy for myeloma treatment. ABSTRACT: Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLe(a/x)), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a “cloak” that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLe(a/x) induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLe(a/x)-enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLe(a/x)-enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLe(a/x) and platelets in MM disease progression and resistance to therapy.
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spelling pubmed-100936422023-04-13 Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity Natoni, Alessandro Cerreto, Marina De Propris, Maria Stefania Petrucci, Maria Teresa Fazio, Francesca Intoppa, Stefania Milani, Maria Laura Kirkham-McCarthy, Lucy Henderson, Robert Swan, Dawn Guarini, Anna O’Dwyer, Michael Foà, Robin Cancers (Basel) Article SIMPLE SUMMARY: Platelet cloaking of tumor cells has been shown to play an important role in tumor metastasis and immune evasion. Multiple myeloma is a tumor of the plasma cells that colonizes different sites of the axial skeleton, including the skull. Herein, we show that specific carbohydrate structures present on the surface of multiple myeloma cells are essential in mediating direct interaction between the platelets and malignant plasma cells, which can be blocked by targeting P-selectin. Platelet binding to myeloma cells inhibits natural killer cell-mediated cytotoxicity, facilitating tumor immune evasion. We propose that platelets are important players in multiple myeloma dissemination, and targeting myeloma–platelet interactions may represent a novel strategy for myeloma treatment. ABSTRACT: Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLe(a/x)), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a “cloak” that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLe(a/x) induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLe(a/x)-enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLe(a/x)-enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLe(a/x) and platelets in MM disease progression and resistance to therapy. MDPI 2023-04-05 /pmc/articles/PMC10093642/ /pubmed/37046814 http://dx.doi.org/10.3390/cancers15072154 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Natoni, Alessandro
Cerreto, Marina
De Propris, Maria Stefania
Petrucci, Maria Teresa
Fazio, Francesca
Intoppa, Stefania
Milani, Maria Laura
Kirkham-McCarthy, Lucy
Henderson, Robert
Swan, Dawn
Guarini, Anna
O’Dwyer, Michael
Foà, Robin
Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity
title Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity
title_full Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity
title_fullStr Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity
title_full_unstemmed Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity
title_short Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity
title_sort sialofucosylation enables platelet binding to myeloma cells via p-selectin and suppresses nk cell-mediated cytotoxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093642/
https://www.ncbi.nlm.nih.gov/pubmed/37046814
http://dx.doi.org/10.3390/cancers15072154
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