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Direct targeting of genetically modified tumour cells to FcγRI triggers potent tumour cytotoxicity
Author(s) -
Bevaart Lisette,
Goldstein Joel,
Vitale Laura,
Russoniello Christina,
Treml John,
Zhang Jun,
Graziano Robert F.,
Leusen Jeanette H. W.,
Winkel Jan G. J.,
Keler Tibor
Publication year - 2006
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05884.x
Subject(s) - biology , cytotoxicity , effector , cd64 , microbiology and biotechnology , transfection , antibody , secretion , tumor necrosis factor alpha , cytokine , cancer research , cell culture , immunology , in vitro , biochemistry , genetics
Summary Expression of the type I receptor for Fc domain of immunoglobulin (Ig)G (Fc γ RI or CD64) is restricted to myeloid effector cells, such as monocytes, macrophages and a subset of dendritic cells. Previous work has indicated a role for Fc γ RI in antibody‐dependent phagocytosis and lysis of tumour cells. We hypothesised that tagging of tumour cells with an anti‐Fc γ RI single chain Fv (sFv) may facilitate targeting to this receptor on effector cells, thereby initiating tumour cytotoxicity. A vector encoding the sFv for an Fc γ RI‐specific antibody (H22), linked to the transmembrane domain of platelet‐derived growth factor was constructed. Transfected tumour cells expressed high surface levels of functional H22‐sFv, which greatly enhanced susceptibility for phagocytosis and lysis by monocytes and macrophages. The expression of H22‐sFv evoked the ability of tumour cells to directly activate monocytes, as evidenced by phosphorylation of mitogen‐activated protein kinase and secretion of the inflammatory cytokines interleukin (IL)‐1 β , tumour necrosis factor‐ α and IL‐6. Moreover, growth of tumour cells in mice expressing H22‐sFv was profoundly delayed (or absent) in transgenic mice expressing human Fc γ RI. These results demonstrated that tumour cells can be readily modified to activate cell effector mechanisms, a strategy that may be useful for in vivo targeting in patients.