title: Tn glycosylation of the MUC6 protein modulates its immunogenicity and promotes the induction of Th17-biased T cell responses.
abstract: The Tn antigen (α-GalNAc-O-Ser/Thr) is one of the most specific human cancer-associated structures. This antigen, together with mucins, the major carriers of O-glycosylated tumor antigens in adenocarcinomas, are being evaluated as anti-cancer immunotherapeutic targets. In particular, the MUC6 protein, which is normally expressed only in gastric tissues, has been detected in intestinal, pulmonary, colorectal, and breast carcinomas. To develop anti-cancer vaccines based on the Tn antigen, we produced MUC6 proteins with different Tn density by using mixtures of recombinant ppGalNAc-T1, -T2, and -T7. The obtained glycoproteins were characterized and analyzed for their immunological properties, as compared with the non-glycosylated MUC6. We show that these various MUC6:Tn glycoproteins were well recognized by both MUC6 and Tn-specific antibodies. However, Tn glycosylation of the MUC6 protein strongly affected their immunogenicity by partially abrogating Th1 cell responses, and promoting IL-17 responses. Moreover, the non-glycosylated MUC6 was more efficiently presented than MUC6:Tn glycoproteins to specific T CD4(+) hybridomas, suggesting that Tn glycosylation may affect MUC6 processing or MHC binding of the processed peptides. In conclusion, our results indicate that Tn glycosylation of the MUC6 protein strongly affects its B and T cell immunogenicity, and might favor immune escape of tumor cells.
authors.affiliation: From the Institut Pasteur, Department of Immunology, Immune Regulation and Vaccinology Unit, 75015 Paris,; INSERM, U1041, Paris,; the Institut Pasteur, Département de Biologie Structurale et Chimie, Unité de Chimie des Biomolécules, 75015 Paris, and; the CNRS, URA 2128, Paris, France.
authors.forename: Teresa
authors.initials: T
authors.lastname: Freire
authors.affiliation: From the Institut Pasteur, Department of Immunology, Immune Regulation and Vaccinology Unit, 75015 Paris,; INSERM, U1041, Paris.
authors.forename: Richard
authors.initials: R
authors.lastname: Lo-Man
authors.affiliation: the Institut Pasteur, Département de Biologie Structurale et Chimie, Unité de Chimie des Biomolécules, 75015 Paris, and; the CNRS, URA 2128, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bay
authors.affiliation: From the Institut Pasteur, Department of Immunology, Immune Regulation and Vaccinology Unit, 75015 Paris,; INSERM, U1041, Paris,. Electronic address: claude.leclerc@pasteur.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D005260:Female; D006031:Glycosylation; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D055272:Mucin-6 / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000912:Antibodies, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines; D020381:Interleukin-17; C524734:MUC6 protein, human; D055272:Mucin-6; C040286:Tn antigen