Controlling T-Cell Activation with Synthetic Dendritic Cells Using the Multivalency Effect

Abstract

Artificial antigen-presenting cells (aAPCs) have recently gained a lot of attention. They efficiently activate T cells and serve as powerful replacements for dendritic cells in cancer immunotherapy. Focusing on a specific class of polymer-based aAPCs, so-called synthetic dendritic cells (sDCs), we have investigated the importance of multivalent binding on T-cell activation. Using antibody-functionalized sDCs, we have tested the influence of polymer length and antibody density. Increasing the multivalent character of the antibody-functionalized polymer lowered the effective concentration required for T-cell activation. This was evidenced for both early and late stages of activation. The most important effect observed was the significantly prolonged activation of the stimulated T cells, indicating that multivalent sDCs sustain T-cell signaling. Our results highlight the importance of multivalency for the design of aAPCs and will ultimately allow for better mimics of natural dendritic cells that can be used as vaccines in cancer treatment.

Materials for Immunotherapy

“…In comparison to free antibodies and monofunctional sDCs, the combination of anti‐CD3 and anti‐CD28‐decorated nanoworms: i) enhanced the formation of IS, ii) lowered the effective antibody concentration required for T cell activation, iii) prolonged T cell activation, iv) promoted specific T cell programming, and v) inhibited T regulatory cell activation. In 2017, the same groups investigated the effect of nanoworm length and antibody density on T cell activation . The authors showed that the increased multivalency of the antibody‐functionalized sDCs produced a significant reduction in the threshold of T cell activation.…”

Designing Multivalent Ligands to Control Biological Interactions: From Vaccines and Cellular Effectors to Targeted Drug Delivery

“…As with most multivalent cellular effectors, the T cell activation by sDCs occurred at much lower doses of antibody compared to activation by soluble monomeric ligand (Figure C). Interestingly, interferon release assays indicated that this enhancement was reflected in late stages of T cell activation as well and was sustained for an extended period of time—providing evidence that the multivalent effect goes beyond just an avidity increase …”

“…An important step in the activation of T cells via dendritic cell (DC) binding is the interaction of antigen‐loaded major histocompatibility complexes (pMHCs) of DCs with TCRs. Hammink et al . conjugated anti‐CD3 antibodies, which are known to trigger the TCR, to a semiflexible and linear polyisocyanopeptide scaffold (Figure A) resulting in synthetic dendritic cells (sDCs).…”

“…C) T cell activation occurs at much lower doses of antibody compared to those of freely soluble effector ligands. Figure adapted from with permission. Copyright 2017 American Chemical Society.…”

“…[24] An alternatives trategy to activate Tc ells is to use artificial antigen-presenting cells (aAPCs), which may serve as al ess expensive replacement for dendriticc ell therapy.A ni mportant step in the activation of Tcells via dendritic cell (DC) binding is the interaction of antigen-loaded major histocompatibility complexes (pMHCs) of DCs with TCRs. Hammink et al [25] conjugated anti-CD3 antibodies, which are knownt ot riggert he TCR, to as emiflexible and linear polyisocyanopeptide scaffold ( Figure 4A)r esulting in synthetic dendritic cells (sDCs). The combination of high aspectratio, nanometer size and flexibility mimics the fluidity of the natural cell membrane.…”