Impairment of IgG Fc Functions Promotes Tumor Progression and Suppresses NK Cell Antitumor Actions

Single-hinge cleaved antibodies (scIgGs) in tumors damped NK cell cytotoxic activities and resulted in more aggressive tumor progression, which can be rescued by targeting the neoepitope in scIgGs with an anti-hinge antibody. Natural killer (NK) cells mediate antibody dependent cytotoxic killing of cancer cells via cross-linking Fc gamma R on NK cells with IgG-Fc. Studies have shown that the single-hinge cleaved IgGs (scIgGs) have dysfunctional Fc and failed engagement with Fc gamma Rs on immune cells. However, little is known about how scIgGs impact on antitumor immunity in the tumor microenvironment. In this study, we revealed a significant association of tumor scIgGs with tumor progression and poor outcomes of breast cancer patients (n = 547). Using multiple mouse tumor models, we demonstrated that tumor scIgGs reduced NK cell cytotoxic activities and resulted in aggressive tumor progression. We further showed that an anti-hinge specific monoclonal antibody (AHA) rescued the dysfunctional Fc in scIgGs by providing a functional Fc and restored NK cell cytotoxic activity. These findings point to a novel immunotherapeutic strategy to enhance Fc engagement with Fc gamma Rs for activation of anticancer immunity.