Polymer-Based Synthetic Dendritic Cells for Tailoring Robust and Multifunctional T Cell Responses

Abstract

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.

Materials for Immunotherapy

“…This enabled strong T cell responses at lower concentrations compared to freely soluble antibodies or rigid nanospheres. A follow‐up study was published by the same groups in 2015, showing that sDCs could acquire the essential features of natural dendritic cells via decorating PIC‐based nanoworms with anti‐CD3 and anti‐CD28 . 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.…”

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

“…The cell suspensions were collected at the respective time points (24, 48, 72, 96, and 120 h after the initial stimulation) and used for flow cytometric analysis (CyAn ADP; Beckman Coulter) following the same methodology as described in our previous publications. 22,23 …”

“…Coupling of additional anti-CD28 antibodies (αCD28; signal 2) to the sDC shaped the immunoresponse toward the induction of helper and killer T cells, without activating the regulatory T-cell population. 23 Remarkably, this effect was only seen when both signals were bound to one and the same polyisocyanopeptide backbone, indicating that activation requires both signals to bind in close spatial proximity. These results already provided a first indication that multivalent binding of these sDCs does not only increase the binding strength of the interaction.…”

Surface engineering for lymphocyte programming

“…One way to accomplish this is through the use of a semi-flexible polymer based on poly(isocyano peptides) conjugated with anti-CD3 and anti-CD28 to allow for receptor clustering, as well as efficient multivalent binding [68, 73]. The polymers were able to activate T-Cells at significantly lower concentrations in vitro than rigid spherical poly(lactic- co -glycolic acid) (PLGA) counterparts, but their efficacy and biodistribution in vivo has yet to be studied.…”