Cytokine‐Functionalized Synthetic Dendritic Cells for T Cell Targeted Immunotherapies

Abstract

Widespread application of cytokine-based therapies is hampered by severe toxic side effects, resulting from off-target (immune) cell stimulation. This emphasizes the need for more precise targeting of cytokines to immune cells. While cytokines are generally active as soluble proteins, it is demonstrated here that synthetic mimics of immune cells based on polyisocyanopeptides (PICs), called synthetic dendritic cells (sDCs) can efficiently present immobilized cytokines to T cells, when targeted by anti-CD3 antibodies.Anti-CD3/IL-2-functionalized PICs induce strong T cell activation and proliferation, when compared to PICs functionalized with interleukin-2 (IL-2) alone. In contrast to the semi-flexible PICs, immobilization of IL-2 on a rigid micro-sized scaffold results in significant loss of IL-2 activity, signifying the importance of molecular flexibility on the PIC polymers to maintain function. Similarly, anti-CD3/IFNα-functionalized PICs support long-term proliferation of T cells. Interferon-α containing sDCs additionally promote the development of cytotoxic effector functions of T cells with limited upregulation of the inhibitory immune checkpoint PD-1. This high cytolytic activity and low PD-1expression are essential to maintain effective anti-cancer activity. Together, these results demonstrate that PICs form unique nano-sized scaffolds that efficiently present immobilized cytokines to T cells, thus creating a powerful tool to improve cytokine-based immunotherapies without concomitant off-target toxicity.

Materials for Immunotherapy

“…The authors showed that the increased multivalency of the antibody‐functionalized sDCs produced a significant reduction in the threshold of T cell activation. Recently, a study showed that cytokine‐functionalized nanoworms can be used to trigger T cell responses . The PIC‐based nanoworms were decorated with IL‐2 and anti‐CD3, which stimulated T cell activation and proliferation.…”

Augmentation of T-cell activation by oscillatory forces and engineered antigen-presenting cells

“…Recent work with aAPCs comprising polyisocyanopeptide polymers 100-1000 nm long, functionalized with anti-CD3 and IL-2, showed that closer spacing of the anti-CD3 and IL-2 contributed to T-cell activation (Hammink et al, 2018). These aAPCs together reveal that tuning antigenic signals and spatial separations has utility and offers an advantage over biological antigen presenting cells when developing engineering solutions to scaling the production of T cells for therapeutic purposes.…”

Engineering Biomaterials to Direct Innate Immunity

“…Within the NP core there is also the potential to load cytokines such as IL-2 that induce proliferation of T cells. [55,56] Copyright 2018, John Wiley and Sons and Springer Nature, respectively. [55] One desired element of this modular platform is the flexibility that supports dynamic rearrangement of the signaling cues during T cell interactions.…”