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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-1 expression 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.