In vitro and in vivo characterization of Fc-receptor expression and function on various immune cell subsets

Over the years, the standard care in cancer treatment has changed from surgery, chemotherapy, and/or radiotherapy alone to include the promising field of immunotherapy. Cancer immunotherapy enhances a patient's own immune system to eradicate tumors and/or confer protection from recurrence. The potential of immune complexes (ICs) directly influencing T cells has long been debated, with conflicting reports on T cell expression of Fc[gamma]Rs. Fc[gamma]Rs are inhibiting or activating immune cell receptors that interact with antibodies and can determine the overall outcome of an immune response. Using various methods, we show that several human CD4 and CD8 T cell subsets express Fc[gamma]RII and Fc[gamma]RIII and that IgG ICs suppress T cell proliferation and cytotoxicity. Using an engineered IgG Fc that only binds Fc[gamma]RI but not Fc[gamma]RII/III, we demonstrate that these effects are Fc[gamma]R-mediated. Specifically, whereas memory T cell proliferation was more resistant, naïve T cell proliferation was strongly inhibited by IgG ICs. Nevertheless, IgG ICs significantly diminished effector T cell cytotoxicity. Moreover, we also show that T cells from virally infected and cancer patients display higher levels of surface Fc[gamma]RII/III relative to healthy controls. Finally, human data was followed up with in vitro and in vivo mouse data to demonstrate that murine T cells also express functional Fc[gamma]Rs that can attenuate calcium flux induced by TCR signaling. Confirming that IgG ICs can directly inhibit T cells is essential for the successful design of efficacious and safe therapeutics. Furthermore, we also demonstrate the utility of Fc-engineered antibodies to both enhance and unravel mechanistic insights of immune effector functions like dendritic cell cross presentation or macrophage phagocytosis.Chemical Engineerin