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

Abstract

Three different classes of Fc receptors for IgG (Fc gamma R) are currently distinguished in humans, of which polymorphonuclear phagocytes (PMN) normally express both low-affinity receptor classes-- Fc gamma RII (CD32) and Fc gamma RIII (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 (Fc gamma RI; CD64). For these patients, the relative fluorescence intensity (rFI) for Fc gamma RI 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 Fc gamma RI during G-CSF therapy could be confirmed by using a panel of six CD64-specific antibodies, and by showing mRNA for Fc gamma RI. So far, three genes for Fc gamma RI have been identified, encoding four distinct transcription products. By reverse transcriptase-polymerase chain reaction technology, transcripts for both membrane-associated isoforms (hFc gamma RIa and hFc gamma RIb2) could be detected. The functional activity of Fc gamma RI on PMN during G-CSF therapy was shown by measuring binding of monomeric human IgG and antibody-dependent cellular cytotoxicity (ADCC). Thus, Fc gamma RI-positive neutrophils displayed enhanced ADCC activity to glioma (A1207), squamous cell (A431), and ovarian (SK-ov3) carcinoma cell lines. The involvement of Fc gamma RI in this increased cytotoxic activity was shown by blocking Fc gamma receptors with monoclonal antibodies, and by using F(ab')2 x F(ab')2-bispecific antibodies with specificities against tumor-related antigens and Fc gamma RI, resulting in solely Fc gamma RI-mediated cytotoxicity. Therapeutically, this additional Fc receptor on PMN may increase the efficacy of experimental antibody therapy.

Polymorphonuclear neutrophils and cancer: Intense and sustained neutrophilia as a treatment against solid tumors

“…Importantly, PMN from patients who have been treated with recombinant human G‐CSF also express FcγRI, the high affinity receptor for IgG 119. Consequently, these PMN are more effective in inducing ADCC than are PMN from healthy, untreated donors 120. The receptor for IgA (FcαRI) is also constitutively expressed by PMN and in these cells seems to be the most potent of the Fc receptors for the induction of antibody‐mediated tumor cell killing 121, 122.…”

“…Many of the reports listed in Tables I and II discuss the anticancer effect of PMN via ADCC,27, 41, 46, 50, 64, 83, 116, 120, 122–126, 128, 129, 131–177 and many provide direct evidence of this antibody‐mediated antitumoral role of PMN in vitro. The first reports were published in 1974 and 1975 by Gale and Zighelboim 131, 132.…”

“…(e) The factors stimulating the cytotoxicity of PMN were β‐1,3‐ D glucan, BCG, Propionibacterium acnes , zymosan‐A, Nocardia cell wall skeleton, and OK‐432 53. (f) The MoAb used by Valerius et al120 in the ADCC assays were MoAb 425 a mouse IgG2a to EGFR and the bispecific Ab 520C9x22 against to the erbB2/HER‐2 antigen and to FcγRI. (g) BRM, biologic response modifiers.…”

Chimaeric Lym-1 monoclonal antibody-mediated cytolysis by neutrophils from G-CSF-treated patients: stimulation by GM-CSF and role of Fcγ -receptors

“…Previous studies from various research groups have shown that neutrophils from G-CSF treated patients are more efficient that those from healthy donors in mediating the lysis of various tumour cells sensitised with polyclonal rabbit antiserum (Repp et al, 1991) or murine monoclonal antibodies (Elsässer et al, 1996;Michon et al, 1998;Valerius et al, 1993;Würflein et al, 1998). Among these studies, the findings of Elsaässer and co-workers (Elsässer et al, 1996) and those of Würflein and co-workers (Würflein et al, 1998) are closely related to the present ones.…”

Utility of CD64 on Neutrophils in Orthopedic Infection

“…The expression of CD64 on neutrophils is upregulated as a physiological response to microbial wall components, complement split products, and several cytokines such as interferon-c (IFN-c), interleukin-8 (IL-8), IL-12, and granulocyte-colony stimulating factor (G-CSF). [1][2][3] Therefore, CD64 may be a marker that is specific for infection, and its efficacy in the diagnosis of both systemic and local infections has been reported. [4][5][6] For the diagnosis of musculoskeletal infections seen in orthopedics practice, conventional markers such as CRP or PCT may not be effective.…”