Fc receptors and immunomodulatory antibodies in cancer

The discovery of both cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) as negative regulators of antitumour immunity led to the development of numerous immunomodulatory antibodies as cancer treatments. Preclinical studies have demonstrated that the efficacy of immunoglobulin G (IgG)-based therapies depends not only on their ability to block or engage their targets but also on the antibody's constant region (Fc) and its interactions with Fc gamma receptors (Fc gamma Rs). Fc-Fc gamma R interactions are essential for the activity of tumour-targeting antibodies, such as rituximab, trastuzumab and cetuximab, where the killing of tumour cells occurs at least in part due to these mechanisms. However, our understanding of these interactions in the context of immunomodulatory antibodies designed to boost antitumour immunity remains less explored. In this Review, we discuss our current understanding of the contribution of Fc gamma Rs to the in vivo activity of immunomodulatory antibodies and the challenges of translating results from preclinical models into the clinic. In addition, we review the impact of genetic variability of human Fc gamma Rs on the activity of therapeutic antibodies and how antibody engineering is being utilized to develop the next generation of cancer immunotherapies. Numerous immunomodulatory antibodies for cancer treatment have been developed following the discovery of negative regulators of antitumour immunity such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4). The efficacy of these antibodies is determined not only by their ability to block or engage their target but also by their interactions with Fc gamma receptors (Fc gamma Rs). This Review outlines our current knowledge of these interactions and discusses how we can use this knowledge to generate more effective cancer immunotherapies in the future.