Abstract
Antibody-dependent cellular cytotoxicity (ADCC) is one means by which macrophages (as well as natural killer cells and granulocytes) elicit a cytotoxic response. This is achieved via interaction of the Fc-gamma-receptor (CD64) with the Fc portion of antibody bound to target cells. We have created a chimeric CD64 molecule that incorporates a single chain Fv molecule, targeted against human carcinoembryonic antigen (CEA), fused to the membrane spanning and cytosolic domains of human CD64. Following adenoviral transfer to primary human monocytes, this chimeric CD64 receptor induced antigen-specific cytokine secretion during culture on immobilised CEA protein or on CEA-expressing tumour cells. Moreover, CEA targeted, but not control, monocytes effectively retarded CEA-positive tumour cell growth in vitro. Importantly, targeted monocyte cultures significantly reduced in vivo tumour growth rates in xenograft studies resulting in improved survival rates over that of control monocyte cultures. These data suggest that genetically directing monocytes against tumour antigens may be a useful means of achieving an immunotherapeutic response.
Highlights
Macrophages constitute an important component of the innate immune system playing a key role in linking innate immunity with the adaptive immune system
The cDNA encoding the chimeric Fc-g-receptor was introduced into a firstgeneration recombinant adenoviral vector and expressed under the control of the human cytomegalovirus promoter (RAd.MFE23.hFc.CD64)
MFE23.hFc.CD64 were used to transduce GM-CSF stimulated monocytes derived from human peripheral blood mononuclear cells (PBMCs) by plastic adherence and subsequent 2 day stimulated with recombinant GM-CSF (10 ng/ml)
Summary
Macrophages constitute an important component of the innate immune system playing a key role in linking innate immunity with the adaptive immune system. The presence of high numbers of TAMs in tumours is associated with a poor clinical prognosis, suggesting that TAMs possess powerful mechanisms to traffic to tumour yet are unable to mount an effective antitumour immune response once congregated within the tumour. Antibody-dependent cellular cytotoxicity (ADCC) is one mechanism that macrophages can employ for direct antitumour activity.[9,10,11] A requirement for ADCC is the generation of tumour-binding antibodies, which can be recognised by macrophages through their Fc receptors. It has been demonstrated that Fc-g receptors play a critical role in mediating tumour cytotoxicity in vivo and enhancement of FC-gR-mediated ADCC by inflammatory cells is a key step in development of effective immunotherapeutics.[12]
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