Direct targeting of genetically modified tumour cells to Fc gammaRI triggers potent tumour cytotoxicity.
Expression of the type I receptor for Fc domain of immunoglobulin (Ig)G (Fc gammaRI 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 gammaRI in antibody-dependent phagocytosis and lysis of tumour cells. We hypothesised that tagging of tumour cells with an anti-Fc gammaRI 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 gammaRI-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)-1beta, tumour necrosis factor-alpha and IL-6. Moreover, growth of tumour cells in mice expressing H22-sFv was profoundly delayed (or absent) in transgenic mice expressing human Fc gammaRI. 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.
Bevaart
Lisette
L
Immunotherapy Laboratory, Department of Immunology, University Medical Centre Utrecht, Lundlaan, Utrecht, The Netherlands.
Goldstein
Joel
J
Vitale
Laura
L
Russoniello
Christina
C
Treml
John
J
Zhang
Jun
J
Graziano
Robert F
RF
Leusen
Jeanette H W
JH
van de Winkel
Jan G J
JG
Keler
Tibor
T
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000912:Antibodies, Neoplasm; D007375:Interleukin-1; D015850:Interleukin-6; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C081931:MAK protein, human; C509962:Mak protein, mouse