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