通过逆转 TGF-β 信号增强免疫抑制性肿瘤微环境中 CAR-T 细胞功能

The immunosuppressive tumor microenvironment represents a key challenge for chimeric antigen receptor (CAR) T cells in solid tumors and includes the production of the inhibitory cytokine transforming growth factor (TGF- ), which limits CAR-T cell persistence and function. Current strategies involving the blockade of TGF- signaling have little benefit for solid tumor treatment.

Here, we demonstrate a novel inverted cytokine receptor (ICR)-modified CAR-T cell strategy not only TGF- signal blockade but also antitumor efficacy enhancement. The newly designed T cells carry an ICR construct that fuses the TGF- receptor II extracellular domain to the interleukin-15 (IL-15) receptor cytoplasmic domain (named TB15) and is directed to the tumor antigen epidermal growth factor receptor by a CAR construct.

In mice with high TGF- solid tumors, our signal-inverted CAR/TB15 T cells effectively treat tumors by blocking TGF- and repurposing IL-15 stimulative signaling, resulting in enhanced CAR-T cell persistence and function. As a proof of concept, our study results extend synthetic receptor signaling beyond CAR-directed killing, which could endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumors by using a chimeric ICR.