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Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells
Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals an...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10279866/ https://www.ncbi.nlm.nih.gov/pubmed/37346044 http://dx.doi.org/10.3389/fimmu.2023.1178817 |
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author | Lustig, Marta Chan, Chilam Jansen, J. H. Marco Bräutigam, Maria Kölling, Max A. Gehlert, Carina Lynn Baumann, Niklas Mester, Simone Foss, Stian Andersen, Jan Terje Bastian, Lorenz Sondermann, Peter Peipp, Matthias Burger, Renate Leusen, Jeanette H. W. Valerius, Thomas |
author_facet | Lustig, Marta Chan, Chilam Jansen, J. H. Marco Bräutigam, Maria Kölling, Max A. Gehlert, Carina Lynn Baumann, Niklas Mester, Simone Foss, Stian Andersen, Jan Terje Bastian, Lorenz Sondermann, Peter Peipp, Matthias Burger, Renate Leusen, Jeanette H. W. Valerius, Thomas |
author_sort | Lustig, Marta |
collection | PubMed |
description | Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy. |
format | Online Article Text |
id | pubmed-10279866 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-102798662023-06-21 Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells Lustig, Marta Chan, Chilam Jansen, J. H. Marco Bräutigam, Maria Kölling, Max A. Gehlert, Carina Lynn Baumann, Niklas Mester, Simone Foss, Stian Andersen, Jan Terje Bastian, Lorenz Sondermann, Peter Peipp, Matthias Burger, Renate Leusen, Jeanette H. W. Valerius, Thomas Front Immunol Immunology Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy. Frontiers Media S.A. 2023-06-06 /pmc/articles/PMC10279866/ /pubmed/37346044 http://dx.doi.org/10.3389/fimmu.2023.1178817 Text en Copyright © 2023 Lustig, Chan, Jansen, Bräutigam, Kölling, Gehlert, Baumann, Mester, Foss, Andersen, Bastian, Sondermann, Peipp, Burger, Leusen and Valerius https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Lustig, Marta Chan, Chilam Jansen, J. H. Marco Bräutigam, Maria Kölling, Max A. Gehlert, Carina Lynn Baumann, Niklas Mester, Simone Foss, Stian Andersen, Jan Terje Bastian, Lorenz Sondermann, Peter Peipp, Matthias Burger, Renate Leusen, Jeanette H. W. Valerius, Thomas Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
title | Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
title_full | Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
title_fullStr | Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
title_full_unstemmed | Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
title_short | Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
title_sort | disruption of the sialic acid/siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10279866/ https://www.ncbi.nlm.nih.gov/pubmed/37346044 http://dx.doi.org/10.3389/fimmu.2023.1178817 |
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