Differential effect of cytokine treatment on Fc alpha receptor I- and Fc gamma receptor I-mediated tumor cytotoxicity by monocyte-derived macrophages.
Macrophages represent an important effector cell for Ab-mediated tumor therapy. Previous studies have documented that cytokines can influence Fc receptor (FcR) expression and function. In this study we examined the tumoricidal activities of the type I receptors for IgG (Fc gamma RI) and the IgA FcR (Fc alpha RI) on monocyte-derived macrophages (MDM) cultured in the presence of IFN-gamma, M-CSF, or GM-CSF. Bispecific Abs were used to target a Her2/neu breast carcinoma cell line, SKBR-3, to Fc alpha RI or Fc gamma RI on MDM. Although Fc alpha RI and Fc gamma RI share a common signaling pathway contingent on association with the gamma-chain (FcR gamma subunit), a marked difference in their efficiency in mediating tumoricidal functions was seen in response to specific cytokines. M-CSF- and GM-CSF-treated MDM mediated efficient phagocytosis of SKBR-3 cells by Fc alpha RI and Fc gamma RI; however, IFN-gamma-treated MDM phagocytosed tumor cells only with the Fc gamma RI-directed bispecific Abs. Similarly, IFN-gamma-cultured MDM lysed tumor cells more efficiently via Fc gamma RI then by Fc alpha RI as measured in Ab-dependent cellular cytotoxicity assays. Conversely, GM-CSF-treated MDM mediated more efficient lysis of tumor cells via Fc alpha RI than Fc gamma RI, while M-CSF-cultured MDM were relatively less efficient in mediating Ab-dependent cellular cytotoxicity through either receptor. With the exception of IFN-gamma-mediated enhancement of Fc gamma RI expression and Fc gamma RI gamma-chain complexes, the regulation of Fc gamma RI- or Fc alpha RI-mediated activity occurred without significant change in either receptor expression or total complexes with gamma subunit. These data suggest that the efficiency of Ab-mediated tumor therapy, which depends on FcR effector cell functions, may be modified by the use of specific cytokines.
Keler
T
T
Medarex, Inc., Annandale, NJ 08801, USA. tkeler@injersey.com
Wallace
P K
PK
Vitale
L A
LA
Russoniello
C
C
Sundarapandiyan
K
K
Graziano
R F
RF
Deo
Y M
YM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D018033:Antibodies, Bispecific / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015703:Antigens, CD / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology*; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D011961:Receptors, Fc / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000276:immunology
D000276:Adjuvants, Immunologic; D018033:Antibodies, Bispecific; D015703:Antigens, CD; D016207:Cytokines; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc; D017452:Receptors, IgG