双特异性 DC-T 细胞衔接器在小鼠中重新激活耗竭的肿瘤浸润 T 细胞

Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response.

However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear.

Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor.

Mechanistically, BiDT reactivates exhausted TIM3 + TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment.

Finally, to mitigate IFN -induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFN and report potent antitumor activity with reduced systemic toxicity.

Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.