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

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

doi:10.1002/eji.201142086

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

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

Department of Cellular and Molecular Medicine

52 Citations (Scopus)

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.

Original language	English
Journal	Central-European Journal of Immunology
Volume	42
Issue number	4
Pages (from-to)	936-45
Number of pages	10
ISSN	1426-3912
DOIs	https://doi.org/10.1002/eji.201142086
Publication status	Published - Apr 2012

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "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.",

keywords = "Acetylglucosamine, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Calcium, Cancer Vaccines, Cells, Cultured, Dendritic Cells, Humans, Lectins, C-Type, Lymphocyte Activation, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mucin-1, NF-kappa B, Phosphorylation, Up-Regulation",

author = "Chiara Napoletano and Zizzari, {Ilaria G} and Aurelia Rughetti and Hassan Rahimi and Tatsuro Irimura and Henrik Clausen and Wandall, {Hans H} and Francesca Belleudi and Filippo Bellati and Luca Pierelli and Luigi Frati and Marianna Nuti",

note = "{\textcopyright} 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2012",

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doi = "10.1002/eji.201142086",

language = "English",

volume = "42",

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T1 - Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation

AU - Napoletano, Chiara

AU - Zizzari, Ilaria G

AU - Rughetti, Aurelia

AU - Rahimi, Hassan

AU - Irimura, Tatsuro

AU - Clausen, Henrik

AU - Wandall, Hans H

AU - Belleudi, Francesca

AU - Bellati, Filippo

AU - Pierelli, Luca

AU - Frati, Luigi

AU - Nuti, Marianna

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

KW - Acetylglucosamine

KW - Antigens, Neoplasm

KW - CD8-Positive T-Lymphocytes

KW - Calcium

KW - Cancer Vaccines

KW - Cells, Cultured

KW - Dendritic Cells

KW - Humans

KW - Lectins, C-Type

KW - Lymphocyte Activation

KW - MAP Kinase Signaling System

KW - Mitogen-Activated Protein Kinase 1

KW - Mitogen-Activated Protein Kinase 3

KW - Mucin-1

KW - NF-kappa B

KW - Phosphorylation

KW - Up-Regulation

U2 - 10.1002/eji.201142086

DO - 10.1002/eji.201142086

M3 - Journal article

C2 - 22531918

SN - 1426-3912

VL - 42

SP - 936

EP - 945

JO - Central-European Journal of Immunology

JF - Central-European Journal of Immunology

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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