T cells expressing modified Fc receptor infiltrate solid tumors and provide long-term anti-tumor protection

The clinical success of T cells armed with chimeric antigen receptor (CAR-T) to cure patients with hematological malignancies, has demonstrated the immense therapeutic potential of equipping T cells with synthetic receptors. Nonetheless, the scarcity of tumor-specific antigens and the limited capacity of T cells to infiltrate the tumor microenvironment significantly limit its clinical use in solid tumors. Here, we provide evidence of FcγRI expressing CD8+ T cells presence in both mouse and human tumors as well as inflammation sites. Inspired by this discovery, we engineered a novel FcγRI-based receptor for T cells. This design allows T cells to target tumor cells indirectly through antibody intermediates, separating the processes of antigen recognition and T cell activation. This approach allows T cells to initiate killing exclusively against cells with antigen overexpression, thus minimizing on-target off-tumor cytotoxicity. Interestingly, the modified FcγRI expression in T cells unexpectedly induces constitutive expression of the CD11b integrin. This additional effect enables the engineered T cells to efficiently infiltrate the tumor basement membrane and develop an effector memory phenotype, potentially promoting long-term anti-tumor activity. The presence of these effector memory subsets characterized complete responders and mediated tumor regression upon rechallenge. Overall, T cell-mediated ADCC suggests an alternative, novel strategy for conventional CAR-T cell design, enables T cells to differentiate between target cells expressing the same antigen, and overcomes the physical barriers of the tumor microenvironment.