Microvesicle Cargo of Tumor-Associated MUC1 to Dendritic Cells Allows Cross-presentation and Specific Carbohydrate Processing

Abstract

Tumor-associated glycoproteins are a group of antigens with high immunogenic interest: The glycoforms generated by the aberrant glycosylation are tumor-specific and the novel glycoepitopes exposed can be targets of tumor-specific immune responses. The MUC1 antigen is one of the most relevant tumor-associated glycoproteins. In cancer, MUC1 loses polarity and becomes overexpressed and hypoglycosylated. Changes in glycan moieties contribute to MUC1 immunogenicity and can modify the interactions of tumor cells with antigen-presenting cells such as dendritic cells that would affect the overall antitumor immune response. Here, we show that the form of the MUC1 antigen, i.e., soluble or as microvesicle cargo, influences MUC1 processing in dendritic cells. In fact, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment and is presented by dendritic cells to MUC1-specific CD8 þ T cells stimulating IFN-g responses, whereas the soluble MUC1 is retained in the endolysosomal/HLA-II compartment independently by the glycan moieties and by the modality of internalization (receptor-mediated or non-receptor mediated). MUC1 translocation to the HLA-I compartment is accompanied by deglycosylation that generates novel MUC1 glycoepitopes. Microvesicle-mediated transfer of tumor-associated glycoproteins to dendritic cells may be a relevant biologic mechanism in vivo contributing to define the type of immunogenicity elicited. Furthermore, these results have important implications for the design of glycoprotein-based immunogens for cancer immunotherapy.

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

“…PD-L1 decreased in the DCs after maturation, as compared with untreated mature DCs or DCs differentiated in the presence of sunitinib. PD-L1 was expressed in microvesicles released by DCs confirming the role of cell particles in delivering remote signaling (37). The phenotypic changes observed in the pazopanib-treated DCs were accompanied with biological behavior consistent with an immune priming effect.…”

Focus on Extracellular Vesicles: New Frontiers of Cell-to-Cell Communication in Cancer

“…Rughetti and colleagues characterized a population of EVs containing the tumor associated MUC1, a glycoprotein that can bind the MHC groove and induce activation of CD8+ T cells, which can influence its processing, in dendritic cells. Importantly, dendritic cells can also internalize MUC1-positive EVs obtained from ascites of patients with stage III or IV ovarian cancer [ 78 ]. It is evident that, by eliminating the lymphocytes that have the ability to recognize and kill tumor cells, or by activating the regulatory suppressive branch of the adaptive response, cancer can escape immune attack and enhance its own survival [ 79 ].…”

MGL Receptor and Immunity: When the Ligand Can Make the Difference

“…Employing the Tn-MUC1 glycoform as cancer model glycoantigen, we showed that the structure of the MGL ligand dictates the upcoming intracellular processing. In fact, upon MGL engagement, the large soluble recombinant Tn-MUC1 glycoprotein (Tn-MUC1 16TR ) corresponding to the one shed in vivo by epithelial cancers remained trapped in the endolysosomal/HLAII compartment, while the MUC1 peptide (Tn-MUC1 3TR ), 60 amino acids long, carrying 9 Tn moles colocalized both in HLAII and HLAI compartments [ 16 , 57 ] ( Figure 3(a) ).…”