Microvesicle cargo of tumor-associated MUC1 to dendritic cells allows cross-presentation and specific carbohydrate processing.
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(+) T cells stimulating IFN-γ 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.
Authors' Affiliations: Departments of Research Oncology, King's College of London, Guy's Hospital, London, United Kingdom.
Aurelia
A
Rughetti
Hassan
H
Rahimi
Francesca
F
Belleudi
Chiara
C
Napoletano
Federico
F
Battisti
Ilaria G
IG
Zizzari
Morena
M
Antonilli
Filippo
F
Bellati
Hans H
HH
Wandall
Pierluigi
P
Benedetti Panici
Joy M
JM
Burchell
Mara R
MR
Torrisi
Marianna
M
Nuti
D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D022162:Cytoplasmic Vesicles / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006031:Glycosylation; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008247:Lysosomes / Q000276:immunology; D018396:Mucin-1 / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D012995:Solubility; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C060192:MUC1 protein, human; D018396:Mucin-1; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma