The high affinity Fc receptor provides a unique scaffold for directing T cells against solid cancers

The pioneering design of chimeric antigen receptors T-cells (CAR-T) therapy has revolutionized treatments of refractory lymphomas and demonstrated the potential in reprogramming the immune system. Nonetheless, exhaustion, cytotoxicity and suppressive tumor microenvironment limit their efficacy in solid tumors. Moreover, the high sensitivity f CART cells dictate directing it against antigens exclusively expressed on tumor cells. Recently, we characterized a novel subset of tumor-infiltrating CD4 + T-cells that express the high-affinity FcγRI receptor and are capable of antibody-mediated cell cytotoxicity. Here, we provide further analysis of their biology and prevalence in human diseases. We also provide evidences for the presence of CD8 + T cells expressing FcγRI in tumors. While endogenous FcγRI is expressed on exhausted and non-proliferative T cells, ectopic expression in naïve T cells endow them with ADCC capacities. Based on the FcγRI structure, we engineered a novel receptor, allowing T-cells to target tumor cells using antibody intermediates, without the need of TCR recognition. Antibodies provides an ideal mean to discriminate between cells that express high and physiological levels of antigens. Modifications to FcγRI signaling can tune the activation threshold required to elicit T cell cytotoxicity. Here, we further demonstrate the principles and considerations underlying the improvement of the signals transmitted through it. Overall, this work describes the benefits of separating the antigen-binding receptor from the signaling chain and suggests FcRI as a scaffold for cell therapy to overcome CAR T limitations in the treatment of solid tumors. Gene profile comparison between CD64 positive and negative CD4+ T cells from two patients with tonsillitis