title: Antibodies against growth factor receptors can inhibit the proliferation of transformed cells via a cis-interaction with inhibitory FcR.
abstract: When dimerized by Stem Cell Factor (SCF), the Receptor Tyrosine Kinase Kit triggers the proliferation of hematopoietic progenitors, including pro-B cells, and of some differentiated cells, including mast cells. We found previously that anti-Kit antibodies can mimic SCF and that anti-Kit-induced mast cell proliferation can be inhibited by the low-affinity IgG receptors FcγRIIB, when the two receptors are co-aggregated by IgG immune complexes. We show here that the same immune complexes inhibited anti-Kit-induced proliferation of Ba/F3 pro-B cells expressing wt Kit and FcγRIIB and that inhibition required the intracytoplasmic domain of FcγRIIB. Constitutively active Kit mutants are oncogenic. We show that Kit-dependent, ligand-independent proliferation of Ba/F3 cells expressing a constitutively dimerized Kit mutant was also inhibited by IgG immune complexes via FcγRIIB. FcγRIIB-dependent negative regulation therefore also affects Kit-dependent proliferation of transformed cells. Interestingly, the co-aggregation of Kit with FcγRIIB by immune complexes containing SCF also inhibited both growth factor-dependent and growth factor-independent proliferation of Ba/F3 cells expressing wt or mutated Kit, respectively. These results provide the basis for novel immunotherapeutical approaches of FcγRIIB-expressing tumors.
authors.affiliation: Institut Pasteur, Département d’Immunologie, Unité d’Allergologie Moléculaire & Cellulaire, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Malbec
authors.forename: Marc
authors.initials: M
authors.lastname: Daëron
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000918:Antibody Specificity; D049109:Cell Proliferation; D008024:Ligands; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology*; D017978:Receptors, Growth Factor / Q000276:immunology*
chemical_list: D000906:Antibodies; D008024:Ligands; D011961:Receptors, Fc; D017978:Receptors, Growth Factor; D019009:Proto-Oncogene Proteins c-kit