SIGLEC-5/14 Inhibits CD11b/CD18 Integrin Activation and Neutrophil-Mediated Tumor Cell Cytotoxicity

Since the successful introduction of checkpoint inhibitors targeting the adaptive immune system, monoclonal antibodies inhibiting CD47-SIRPα interaction have shown promise in enhancing anti-tumor treatment efficacy. Apart from SIRPα, neutrophils express a broad repertoire of inhibitory receptors, in...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-12, Vol.24 (24), p.17141
Main Authors: Bouti, Panagiota, Blans, Colin, Klein, Bart J A M, Shome, Debarati, Nadafi, Reza, Van Houdt, Michel, Schornagel, Karin, Verkuijlen, Paul J J H, Roos, Virginie, Reijmers, Rogier M, Van Bruggen, Robin, Kuijpers, Taco W, Matlung, Hanke L
Format: Article
Language:English
Subjects:
Acids
Antibodies
antibody therapy
Antigens
Cancer therapies
Cells
checkpoint blockade
Cytotoxicity
Immune system
neutrophil ADCC
Neutrophils
Proteins
sialic acid
SIGLEC
Tumors
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Summary:Since the successful introduction of checkpoint inhibitors targeting the adaptive immune system, monoclonal antibodies inhibiting CD47-SIRPα interaction have shown promise in enhancing anti-tumor treatment efficacy. Apart from SIRPα, neutrophils express a broad repertoire of inhibitory receptors, including several members of the sialic acid-binding receptor (SIGLEC) family. Here, we demonstrate that interaction between tumor cell-expressed sialic acids and SIGLEC-5/14 on neutrophils inhibits antibody-dependent cellular cytotoxicity (ADCC). We observed that conjugate formation and trogocytosis, both essential processes for neutrophil ADCC, were limited by the sialic acid-SIGLEC-5/14 interaction. During neutrophil-tumor cell conjugate formation, we found that inhibition of the interaction between tumor-expressed sialic acids and SIGLEC-5/14 on neutrophils increased the CD11b/CD18 high affinity conformation. By dynamic acoustic force measurement, the binding between tumor cells and neutrophils was assessed. The interaction between SIGLEC-5/14 and the sialic acids was shown to inhibit the CD11b/CD18-regulated binding between neutrophils and antibody-opsonized tumor cells. Moreover, the interaction between sialic acids and SIGLEC-5/14-consequently hindered trogocytosis and tumor cell killing. In summary, our results provide evidence that the sialic acid-SIGLEC-5/14 interaction is an additional target for innate checkpoint blockade in the tumor microenvironment.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms242417141