Mannose receptor (MR) engagement by mesothelin GPI anchor polarizes tumor-associated macrophages and is blocked by anti-MR human recombinant antibody.

Details

Serval ID
serval:BIB_6DD161C4CAA4
Type
Article: article from journal or magazin.
Collection
Publications
Title
Mannose receptor (MR) engagement by mesothelin GPI anchor polarizes tumor-associated macrophages and is blocked by anti-MR human recombinant antibody.
Journal
PloS one
Author(s)
Dangaj D., Abbott K.L., Mookerjee A., Zhao A., Kirby P.S., Sandaltzopoulos R., Powell D.J., Lamazière A., Siegel D.L., Wolf C., Scholler N.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2011
Peer-reviewed
Oui
Volume
6
Number
12
Pages
e28386
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish
Abstract
Tumor-infiltrating macrophages respond to microenvironmental signals by developing a tumor-associated phenotype characterized by high expression of mannose receptor (MR, CD206). Antibody cross-linking of CD206 triggers anergy in dendritic cells and CD206 engagement by tumoral mucins activates an immune suppressive phenotype in tumor-associated macrophages (TAMs). Many tumor antigens are heavily glycosylated, such as tumoral mucins, and/or attached to tumor cells by mannose residue-containing glycolipids (GPI anchors), as for example mesothelin and the family of carcinoembryonic antigen (CEA). However, the binding to mannose receptor of soluble tumor antigen GPI anchors via mannose residues has not been systematically studied. To address this question, we analyzed the binding of tumor-released mesothelin to ascites-infiltrating macrophages from ovarian cancer patients. We also modeled functional interactions between macrophages and soluble mesothelin using an in vitro system of co-culture in transwells of healthy donor macrophages with human ovarian cancer cell lines. We found that soluble mesothelin bound to human macrophages and that the binding depended on the presence of GPI anchor and of mannose receptor. We next challenged the system with antibodies directed against the mannose receptor domain 4 (CDR4-MR). We isolated three novel anti-CDR4-MR human recombinant antibodies (scFv) using a yeast-display library of human scFv. Anti-CDR4-MR scFv #G11 could block mesothelin binding to macrophages and prevent tumor-induced phenotype polarization of CD206(low) macrophages towards TAMs. Our findings indicate that tumor-released mesothelin is linked to GPI anchor, engages macrophage mannose receptor, and contributes to macrophage polarization towards TAMs. We propose that compounds able to block tumor antigen GPI anchor/CD206 interactions, such as our novel anti-CRD4-MR scFv, could prevent tumor-induced TAM polarization and have therapeutic potential against ovarian cancer, through polarization control of tumor-infiltrating innate immune cells.
Keywords
Antibodies/chemistry, Cancer Vaccines/chemistry, Cell Line, Tumor, Coculture Techniques, Female, GPI-Linked Proteins/chemistry, GPI-Linked Proteins/metabolism, Glycosylation, Humans, Lectins, C-Type/chemistry, Lectins, C-Type/metabolism, Macrophages/cytology, Mannose Receptor, Mannose-Binding Lectins/chemistry, Mannose-Binding Lectins/metabolism, Mesothelin, Ovarian Neoplasms/therapy, Phenotype, Protein Binding, Receptors, Cell Surface/chemistry, Receptors, Cell Surface/metabolism, Recombinant Proteins/chemistry, Single-Chain Antibodies/chemistry
Pubmed
Web of science
Open Access
Yes
Create date
04/04/2022 16:54
Last modification date
05/04/2022 5:36
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