title: Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses.
abstract: Dendritic cells (DCs) hold promise for anti-cancer immunotherapy. However, clinically, their efficiency is limited and novel strategies to improve DC-mediated anti-tumor responses are needed. Human DCs display high content of sialic acids, which inhibits their maturation and co-stimulation capacity. Here, we aimed to understand whether exogenous desialylation of DCs improves their anti-tumor immunity. Compared to fully sialylated DCs, desialylated human DCs loaded with tumor-antigens showed enhanced ability to induce autologous T cells to proliferate, to secrete Th1 cytokines, and to specifically induce tumor cell apoptosis. Desialylated DCs showed an increased expression of MHC-I and -II, co-stimulatory molecules and an augmented secretion of IL-12. Desialylated HLA-A*02:01 DCs pulsed with gp100 peptides displayed enhanced peptide presentation through MHC-I, resulting in higher activation ofgp100280-288 specific CD8+ cytotoxic T cells. Desialylated murine DCs also exhibited increased MHC and co-stimulatory molecules and higher antigen cross-presentation via MHC-I. These DCs showed higher ability to activate antigen-specific CD4+ and CD8+ T cells, and to specifically induce tumor cell apoptosis. Collectively, our data demonstrates that desialylation improves DCs' ability to elicit T cell-mediated anti-tumor activity, due to increased MHC-I expression and higher antigen presentation via MHC-I. Sialidase treatment of DCs may represent a technology to improve the efficacy of antigen loaded-DC-based vaccines for anti-cancer immunotherapy.
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Silva
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.|UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal.
authors.forename: Zélia
authors.initials: Z
authors.lastname: Silva
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Graça
authors.initials: G
authors.lastname: Marques
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.|UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Ferro
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Márcia
authors.initials: M
authors.lastname: Gonçalves
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Mauro
authors.initials: M
authors.lastname: Monteiro
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: van Vliet
authors.affiliation: IGC, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Elodie
authors.initials: E
authors.lastname: Mohr
authors.affiliation: IGC, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Andreia C
authors.initials: AC
authors.lastname: Lino
authors.affiliation: UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal.|CQE, Centro Química Estrutural, Instituto Superior Técnico, ULisboa, Lisboa, Portugal.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Fernandes
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Flávia A
authors.initials: FA
authors.lastname: Lima
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
authors.affiliation: StemLab, Cantanhede, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Matos
authors.affiliation: Universidade Vila Velha, Espírito Santo, Brasil.|IGC, Instituto Gulbenkian de Ciência, Oeiras, Portugal.|UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Tadokoro
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.|UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Videira
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D019158:N-Acetylneuraminic Acid
keywords: Th1-polarization; anti-tumor immunity; antigen cross-presentation; dendritic cells; sialic acid