Potentiating CAR-T cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal

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 (3 (TGF-(3), which limits CAR-T cell persistence and function. Current strategies involving the blockade of TGF-(3 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-(3 signal blockade but also antitumor efficacy enhancement. The newly designed T cells carry an ICR construct that fuses the TGF-(3 receptor II extracellular domain to the interleukin-15 (IL-15) receptor a cytoplasmic domain (named TB15) and is directed to the tumor antigen epidermal growth factor receptor by a CAR construct. In mice with high TGF-(3 solid tumors, our signal-inverted CAR/TB15 T cells effectively treat tumors by blocking TGF(3 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.