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

The Fcγ receptors (FcγRs) expressed on hematopoietic cells play a key role in immune defenses by linking humoral and cellular immunity (1). FcγRs display coordinate and opposing roles in immune responses depending on their cytoplasmic region and/or their associated chains. Indeed, the activating receptors contain an immunoreceptor tyrosine-based activation motif (ITAM) and initiate inflammatory, cytolytic, and phagocytic activities of immune effector cells. In contrast, the inhibitory receptors that downmodulate the immune responses contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) (2, 3). Three categories of FcγR exist: FcγRI has high affinity for monomeric IgG, whereas FcγRII and FcγRIII exhibit low affinity for monomeric IgG but avidly bind IgGcontaining immune complexes (ICs). Both in mice and in humans (4), two isoforms of the inhibitory FcγRIIB (FcγRIIB1 and FcγRIIB2) are produced by an alternative splicing, which generates a 47–amino acid insert in the intracellular domain of FcγRIIB1. Antibodies directed against neoplastic cells provide new therapeutic approaches against various malignancies, including lymphoma, leukemia, melanoma, and breast and colorectal carcinoma (5, 6). There is increasing evidence that the Fc portion of the anti-tumor IgG is a major component of their therapeutic activity, along with other mechanisms such as activation of apoptosis, blockade of signaling pathways, or masking of tumor antigens. Thus, by binding to activating FcγRs expressed by immune effector cells, such as macrophages, monocytes, neutrophils, or NK cells, tumor-specific antibodies trigger the destruction of malignant cells via antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (7, 8). Recent experiments have shown that inhibitory FcγR decreases the in vivo efficacy of antibodies against tumors. Indeed, the use of mAb’s to eradicate a variety of tumors in mice reveals that the FcγRIIB inhibitory receptor expressed on effector cells