Modulation of tumor growth by inhibitory Fcγ receptor expressed by human melanoma cells

The efficacy of anti-tumor IgG reflects the balance between opposing signals mediated by activating and inhibitory Fcgamma receptors (FcgammaRs) expressed by effector cells. Here, we show that human malignant melanoma cells express the inhibitory low-affinity Fcgamma receptor FcgammaRIIB1 in 40% of tested metastases. When melanoma cells were grafted in nude mice, a profound inhibition of FcgammaRIIB1 tumor growth that required the intracytoplasmic region of the receptor was observed. IgG immune complexes (ICs) may be required for this inhibition, since sera from nude mice bearing tumors contained IgG that decreased the proliferation of FcgammaRIIB1-positive cells in vitro, and tumor development of FcgammaRIIB1-positive melanoma lines was not inhibited in antibody defective severe combined immunodeficiency (SCID) mice. Passive immunization of SCID mice with anti-ganglioside G(D2) antibody resulted in significant inhibition of growth of FcgammaRIIB1-positive tumors in an intracytoplasmic-dependent manner. Altogether, these data suggest that human melanoma cells express biologically active inhibitory FcgammaRIIB1, which regulates their development upon direct interaction with anti-tumor antibodies. Therefore, FcgammaR expression on human tumors may be one component of the efficacy of antibody-mediated therapies, and FcgammaR-positive tumors could be the most sensitive candidates for such treatments.