IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells.
The anti-tumor activity of recombinant mAb's directed against tumor cell growth receptors has generally been considered to result from direct antiproliferative effects, the induction of apoptosis, or possibly Ab-dependent cellular cytotoxicity mediated against tumor targets. However, it remains unclear to what degree these mechanisms actually aid in the clearance of Ab-coated tumor cells in vivo. We show here that NK cells secrete a distinct profile of potent immunostimulatory cytokines in response to dual stimulation with Ab-coated tumor cells and IL-12. This response could not be duplicated by costimulation with other ILs and was significantly enhanced in the presence of monocytes. Cytokine production was dependent upon synergistic signals mediated by the activating receptor for the Fc portion of IgG (FcgammaRIII) and the IL-12 receptor expressed on NK cells. Coadministration of Ab-coated tumor cells and IL-12 to BALB/c mice resulted in enhanced circulating levels of NK cell-derived cytokines with the capacity to augment anti-tumor immunity. These findings suggest that, in addition to mediating cellular cytotoxicity and apoptosis, the anti-tumor activity of mAb's might also result from activation of a potent cytokine secretion program within immune effectors capable of recognizing mAb-coated targets.
Parihar
Robin
R
Department of Molecular Virology, Immunology, and Medical Genetics, The Arthur G. James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Dierksheide
Julie
J
Hu
Yan
Y
Carson
William E
WE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D017452:Receptors, IgG / Q000502:physiology; D018123:Receptors, Interleukin / Q000502:physiology; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000494:pharmacology; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007371:Interferon-gamma; D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D050797:STAT4 Transcription Factor; D015534:Trans-Activators; D000068878:Trastuzumab; C494090:STAT4 protein, human; C494091:Stat4 protein, mouse