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Tumor cells express pauci- and oligomannosidic N-glycans in glycoproteins recognized by the mannose receptor (CD206)

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Abstract

The macrophage mannose receptor (CD206, MR) is an endocytic lectin receptor which plays an important role in homeostasis and innate immunity, however, the endogenous glycan and glycoprotein ligands recognized by its C-type lectin domains (CTLD) have not been well studied. Here we used the murine MR CTLD4–7 coupled to the Fc-portion of human IgG (MR-Fc) to investigate the MR glycan and glycoprotein recognition. We probed 16 different cancer and control tissues using the MR-Fc, and observed cell- and tissue-specific binding with varying intensity. All cancer tissues and several control tissues exhibited MR-Fc ligands, intracellular and/or surface-located. We further confirmed the presence of ligands on the surface of cancer cells by flow cytometry. To characterize the fine specificity of the MR for glycans, we screened a panel of glycan microarrays. Remarkably, the results indicate that the CTLD4-7 of the MR is highly selective for specific types of pauci- and oligomannose N-glycans among hundreds of glycans tested. As lung cancer tissue and the lung cancer cell line A549 showed intense MR-Fc binding, we further investigated the MR glycoprotein ligands in those cells by immunoprecipitation and glycoproteomic analysis. All enriched glycoproteins, of which 42 were identified, contained pauci- or oligomannose N-glycans, confirming the microarray results. Our study demonstrates that the MR CTLD4-7 is highly selective for pauci- and oligomannosidic N-glycans, structures that are often elevated in tumor cells, and suggest a potential role for the MR in tumor biology.

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Availability of data

The MS proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository [69] with the dataset identifier PXD022546. Glycan microarray data are available in supplementary material and at the NCFG website (https://ncfg.hms.harvard.edu/ncfg-data).

Abbreviations

AEAB:

2-Amino-N-(2-aminoethyl)-benzamide

ACN:

Acetonitrile

CFG:

Consortium for functional glycomics

CR domain:

Cysteine-rich domain

CTLD:

C-type lectin domain

FA:

Formic acid

Fab:

Fragment antigen binding

Fuc:

Fucose

Gal:

Galactose

GalNAc:

N-acetylgalactosamine

Glc:

Glucose

GlcNAc:

N-acetylglucosamine

Hex:

Hexose

HexNAc:

N-acetylhexosamine

HI FBS:

Heat-inactivated fetal bovine serum

IgG:

Immunoglobulin G

LC–MS:

Liquid chromatography-mass spectrometry

mAb100:

Monoclonal antibody 100-4G11-A

Man:

Mannose

MR-Fc:

Mannose receptor-fragment crystallizable

MR, CD206:

Mannose receptor

NeuAc:

N-acetylneuraminic acid

NSCLC:

Non-small cell lung cancer

PaTu-T:

Pa-Tu-8988 T cells

PSG:

Penicillin/Streptomycin/Glutamine

TAM:

Tumor-associated macrophages

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Acknowledgements

We thank Luisa Martinez-Pomares for providing the MR-Fc DNA, Protein Metrics for providing us with a Byonic license for glycopeptide identification and Onur Dagliyan for taking images of the IHC tissue slides.

Funding

This work was supported by the Dutch Research Council (NWO)—Rubicon grant (680–50-1534) to KS and by NIH Grants P41GM103694 and R24GM137763 to RDC.

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Authors and Affiliations

  1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, CLS 11087 - 3 Blackfan Circle, Boston, MA, 02115, USA

    Kathrin Stavenhagen, Chao Gao, Akul Y. Mehta, Jamie Heimburg-Molinaro & Richard D. Cummings

  2. Department of Molecular Cell Biology and Immunology, Amsterdam UMC (VU Medical Center), Amsterdam, The Netherlands

    Kathrin Stavenhagen, Lisa C. Laan & Irma van Die

  3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Jonathan N. Glickman

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  1. Kathrin Stavenhagen
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  8. Richard D. Cummings
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Contributions

KS, LCL and CG performed the experiments. AYM and JHM supported the microarray experiments and analysis. JNG assessed the tissue pathology. KS, IVD, RDC conceptionally designed the work and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Richard D. Cummings.

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Stavenhagen, K., Laan, L.C., Gao, C. et al. Tumor cells express pauci- and oligomannosidic N-glycans in glycoproteins recognized by the mannose receptor (CD206). Cell. Mol. Life Sci. 78, 5569–5585 (2021). https://doi.org/10.1007/s00018-021-03863-1

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