Selective expression of inhibitory Fcγ receptor by metastatic melanoma impairs tumor susceptibility to IgG-dependent cellular response

During melanoma progression, patients develop anti-tumor immunity including the production of anti-tumor antibodies. Although the strategies developed by malignant cells to escape anti-tumor cellular immunity have been extensively investigated, little is known about tumor resistance to humoral immunity. The main effect of IgG antibodies is to activate the immune response by binding to host Fc gamma receptors (Fc gamma R) expressed by immune cells. We previously reported in a limited study that some human metastatic melanoma cells ectopically express the Fc gamma RIIB1, an inhibitory isoform of Fc gamma R. By analyzing a large panel of different types of human primary and metastatic solid tumors, we report herein that expression of Fc gamma RIIB is restricted to melanoma and is acquired during tumor progression. We show that Fc gamma RIIB expression prevents the lysis of human metastatic melanoma cells by NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, independently of the intracytoplasmic region of Fc gamma RIIB. Using experimental mouse models, we demonstrate that expression of Fc gamma RIIB protects B16F0 melanoma tumors from the ADCC induced by monoclonal and polyclonal anti-tumor IgG in vivo. Thus, our results identify Fc gamma RIIB as a marker of human metastatic melanoma that impairs the tumor susceptibility to Fc gamma R-dependent innate effector responses. (C) 2008 Wiley-Liss, Inc.