Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation.

Abstract

Dendritic cells (DCs) sense the microenvironment through several types of receptors recognizing pathogen-associated molecular patterns. In particular, C-type lectins, expressed by distinct subsets of DCs, recognize and internalize specific carbohydrate antigen in a Ca(2+) -dependent manner. Targeting of these receptors is becoming an efficient strategy of delivering antigens in DC-based anticancer immunotherapy. Here we investigated the role of the macrophage galactose type C-lectin receptor (MGL), expressed by immature DCs (iDCs), as a molecular target for α-N-acetylgalactosamine (GalNAc or Tn)-carrying tumor-associated antigens to improve DC performance. MGL expressed by ex vivo-generated iDCs from healthy donors was engaged by a 60-mer MUC1(9Tn) -glycopeptide as a Tn-carrying tumor-associated antigen, and an anti-MGL antibody, as a specific MGL binder. We demonstrated that MGL engagement induced homotrimers and homodimers, triggering the phosphorylation of extracellular signal-regulated kinase 1,2 (ERK1,2) and nuclear factor-κB activation. Analysis of DC phenotype and function demonstrated that MGL engagement improved DC performance as antigen-presenting cells, promoting the upregulation of maturation markers, a decrease in phagocytosis, an enhancement of motility, and most importantly an increase in antigen-specific CD8(+) T-cell activation. These results demonstrate that the targeting of MGL receptor on human DCs has an adjuvant effect and that this strategy can be used to design novel anticancer vaccines.

• Authors: Chiara Napoletano, Ilaria G Zizzari, Aurelia Rughetti, Hassan Rahimi, Tatsuro Irimura, Henrik Clausen, Hans H Wandall, Francesca Belleudi, Filippo Bellati, Luca Pierelli, Luigi Frati, Marianna Nuti
• Journal: European journal of immunology (Eur J Immunol) Vol. 42 Issue 4 Pg. 936-45 (Apr 2012) ISSN: 1521-4141 [Electronic] Germany
• PMID: 22531918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Lectins, C-Type
• MGL lectin, human
• MUC1 protein, human
• Mucin-1
• NF-kappa B
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Calcium
• Acetylglucosamine

Topics

• Acetylglucosamine (immunology, metabolism)
• Antigens, Neoplasm (immunology)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Calcium (immunology, metabolism)
• Cancer Vaccines (immunology)
• Cells, Cultured
• Dendritic Cells (cytology, immunology, metabolism)
• Humans
• Lectins, C-Type (immunology, metabolism)
• Lymphocyte Activation (physiology)
• MAP Kinase Signaling System (immunology)
• Mitogen-Activated Protein Kinase 1 (immunology, metabolism)
• Mitogen-Activated Protein Kinase 3 (immunology, metabolism)
• Mucin-1 (immunology, metabolism)
• NF-kappa B (immunology, metabolism)
• Phosphorylation (immunology)
• Up-Regulation (immunology)