Sialic acid removal from dendritic cells improves antigen cross-presentation and boosts anti-tumor immune responses

Abstract

// Mariana Silva 1,* , Zélia Silva 1,6,* , Graça Marques 1,* , Tiago Ferro 1,6 , Márcia Gonçalves 1 , Mauro Monteiro 1 , Sandra J. van Vliet 2 , Elodie Mohr 4 , Andreia C. Lino 4 , Alexandra R. Fernandes 6,7 , Flávia A. Lima 1 , Yvette van Kooyk 2 , Teresa Matos 5 , Carlos E. Tadokoro 3,4,6,** and Paula A. Videira 1,6,** 1 CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal 2 Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands 3 Universidade Vila Velha, Espírito Santo, Brasil 4 IGC, Instituto Gulbenkian de Ciência, Oeiras, Portugal 5 StemLab, Cantanhede, Portugal 6 UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Portugal 7 CQE, Centro Química Estrutural, Instituto Superior Técnico, ULisboa, Lisboa, Portugal * Co-first authorship ** Co-last authorship Correspondence to: Paula A. Videira, email: // Keywords : dendritic cells, sialic acid, antigen cross-presentation, Th1-polarization, anti-tumor immunity Received : December 09, 2015 Accepted : April 16, 2016 Published : May 17, 2016 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 ofgp100 280–288 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.