T Cells enhance Natural Killer Cell antibody dependent cellular cytotoxicity

Monoclonal antibodies (mAbs) that directly target cancer cells have been clinically effective for over two decades. However, some patients either do not respond or develop resistance over time. The mechanisms behind response or resistance to mAbs are not fully understood. Evidence suggests that antibody-dependent cellular cytotoxicity (ADCC), mediated by natural killer (NK) cells, is a key mechanism of action for many mAbs, including anti-CD20 mAb rituximab (RTX). Previous in vitro studies from our lab suggested a potential mechanism of resistance for mAbs, associated with reduced NK cell-mediated ADCC in the absence of T cells. Studies showed that T cells play an essential role in maintaining the viability and cytotoxicity of NK cells activated by RTX-coated cancer cells. This support is largely dependent on CD4+ T cells, involves direct contact between T cells and NK cells and is mediated in large part by interleukin-2 (IL-2). Therefore, resistance to mAb therapy can result from inadequate T cell help in the tumor microenvironment (TME). Based on this, we hypothesized that T cell help plays a central role in supporting NK cell-mediated ADCC by anti-cancer mAbs. Furthermore, we propose that anti-CD3-based bispecific antibodies (bsAbs) can enhance T cell help within the TME, thereby boosting NK cell-mediated ADCC and improving the efficacy of mAb-based therapies. Additional in vitro studies indicated that activating a small number of T cells using bsAbs targeting CD3 and cancer cells increases IL-2 production, thereby enhancing T cell-mediated support for NK cell viability and ADCC. However all this previous work was conducted in vitro, and whether this mechanism holds true in vivo or can be expanded to other antibodies and cancer models needed further testing.