A Chimera Antigen Receptor Containing TLR4 Signaling Domain Enhances CAR-iMACs Polarization and Potency against Solid Tumors

Chimeric antigen receptor (CAR)-T cell therapies have shown success in treating certain types of hematologic malignancies, but its therapeutic effect on solid tumors is unsatisfactory. Macrophages came to attention because of its phagocytosis function against tumor cells and its immunomodulation capacity. The first generation of engineered CAR-macrophages demonstrated that the CAR can stimulate macrophage phagocytosis function in an antigen dependent way. In this work, we genetically engineered induced pluripotent stem cell (iPSC) derived macrophages (iMACs) with a TLR4 intracellular TIR domain-containing CAR, and achieved enhanced anti-tumor effect. CD3ζ-TIR-CAR, the second generation of TIR-based dual signaling CAR endowed iMACs the target engulfing capacity against antigen-expressing tumor cells, as well as potency of antigen-dependent M1 polarization and resistance to M2 polarization in a NF-κB dependent manner. Taken together, we established the next generation of CAR-iMAC equipped with concurrent antigen-dependent phagocytosis and polarization capacity for better anti-tumor functions.