Involvement of the high-affinity receptor for IgG (FcγRI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy

Abstract

Three different classes of Fc receptors for IgG (FcγR) are currently distinguished in humans, of which polymorphonuclear phagocytes (PMN) normally express both low-affinity receptor classes - FcγRII (CD32) and FcγRIII (CD16). During therapy with granulocyte colony-stimulating factor (G-CSF), neutrophils from patients with various malignancies and different hematologic disorders were found to additionally express high levels of the receptor with high affinity for IgG (FcγRI; CD64). For these patients, the relative fluorescence intensity (rFI) for FcγRI was 5.3 (range, 1.7 to 10.3; n = 19), compared with 1.0 (range, 1.0 to 1.1; n = 8) for healthy donors. The expression of FcγRI during GCSF therapy could be confirmed by using a panel of six CD64-specific antibodies, and by showing mRNA for FcγRI. So far, three genes for FcγRI have been identified, encoding four distinct transcription products. By reverse transcriptase-polymerase chain reaction technology, transcripts for both membrane-associated isoforms (hFcγRIa and hFcγRIb2) could be detected. The functional activity of FcγRI on PMN during G-CSF therapy was shown by measuring binding of monomeric human IgG and antibody-dependent cellular cytotoxicity (ADCC). Thus, FcγRI-positive neutrophils displayed enhanced ADCC activity to glioma (A1207), squamous cell (A431), and ovarian (SK-ov3) carcinoma cell lines. The involvement of FcγRI in this increased cytotoxic activity was shown by blocking FCγ receptors with monoclonal antibodies, and by using F(ab′)2 × F(ab′)2-bispecific antibodies with specificities against tumor-related antigens and FcγRI, resulting in solely FcγRI-mediated cytotoxicity. Therapeutically, this additional Fc receptor on PMN may increase the efficacy of experimental antibody therapy. © 1993 by The American Society of Hematology.