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 Ca2+-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 MUC19Tnglycopeptide 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 ki

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 Ca2+-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 a-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 MUC19Tn-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-?B 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.

Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation / Napoletano, Chiara; Zizzari, ILARIA GRAZIA; Rughetti, Aurelia; RAHIMI KOSHKAKI, Hassan; Tatsuro, Irimura; Henrik, Clausen; Hans H., Wandall; Belleudi, Francesca; Bellati, Filippo; Pierelli, Luca; Frati, Luigi; Nuti, Marianna. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - 42:4(2012), pp. 936-945. [10.1002/eji.201142086]

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

NAPOLETANO, Chiara;ZIZZARI, ILARIA GRAZIA;RUGHETTI, Aurelia;RAHIMI KOSHKAKI, HASSAN;BELLEUDI, Francesca;BELLATI, FILIPPO;PIERELLI, LUCA;FRATI, Luigi;NUTI, Marianna
2012

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 Ca2+-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 MUC19Tnglycopeptide 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 ki
2012
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 Ca2+-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 a-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 MUC19Tn-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-?B 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.
tn-tumor associated antigens; macrophage galactose-type c-type lectin (mgl); muc1; dendritic cells; c-type lectins
01 Pubblicazione su rivista::01a Articolo in rivista
Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation / Napoletano, Chiara; Zizzari, ILARIA GRAZIA; Rughetti, Aurelia; RAHIMI KOSHKAKI, Hassan; Tatsuro, Irimura; Henrik, Clausen; Hans H., Wandall; Belleudi, Francesca; Bellati, Filippo; Pierelli, Luca; Frati, Luigi; Nuti, Marianna. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - 42:4(2012), pp. 936-945. [10.1002/eji.201142086]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/738893
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