Polymer-based synthetic dendritic cells for tailoring robust and multifunctional T cell responses.
Dendritic cells (DCs) are antigen-presenting cells that play an essential role in T cell activation. Recent efforts in cancer immunotherapy have been directed at the development of artificial antigen presenting cells (aAPCs) loaded with tumor antigens. These aAPCs are designed to mimic DCs with the goal of triggering an efficient and specific T cell response directed against the tumor. We have designed a novel synthetic dendritic cell (sDC) that possesses the essential features of natural DCs. Our sDC is based on a semiflexible poly(isocyano peptide) polymer and carries anti-CD3 antibodies (αCD3) for triggering the T cell receptor/CD3 complex as well as anti-CD28 antibodies (αCD28) as a co-stimulatory signal. Multiple copies of both antibodies facilitate multivalent binding similar to natural DCs. The high mobility of these polymer-bound antibodies, reminiscent of protein motility in a natural plasma membrane, enables receptor rearrangements to occur during T cell activation. We show that our bifunctional αCD3/αCD28-sDC triggers T cell activation at significantly lower antibody concentrations than freely soluble antibodies. This superior performance is further demonstrated in comparison to a mixture of monofunctional αCD3-sDC and αCD28-sDC. The presence of both antibodies on the same polymer not only reduces the threshold for T cell activation but, more importantly, critically shapes the specificity of the T cell response. αCD3/αCD28-sDC is a far more efficient activator of multifunctional killer cells. These findings demonstrate the potential of multifunctional polymers for mimicking natural DCs, paving the way for their exploitation in immunotherapeutic strategies.
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Geert Grooteplein 26, 6525 GA Nijmegen, The Netherlands.
Subhra
S
Mandal
Roel
R
Hammink
Jurjen
J
Tel
Zaskia H
ZH
Eksteen-Akeroyd
Alan E
AE
Rowan
Kerstin
K
Blank
Carl G
CG
Figdor
D018106:CD28 Antigens / Q000737:chemistry; D017252:CD3 Complex / Q000737:chemistry; D019496:Cancer Vaccines / Q000737:chemistry; D003713:Dendritic Cells; D006801:Humans; D015394:Molecular Structure; D011108:Polymers / Q000138:chemical synthesis*; D016176:T-Lymphocyte Subsets / Q000502:physiology*
D018106:CD28 Antigens; D017252:CD3 Complex; D019496:Cancer Vaccines; D011108:Polymers