Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis-inducing ligand.
Our recent studies have demonstrated that human immature dendritic cells (DCs) are able to directly and effectively mediate apoptotic killing against a wide array of cultured and freshly-isolated cancer cells without harming normal cells. In the present study, we demonstrate that this tumoricidal activity is mediated by multiple cytotoxic TNF family ligands. We determine that human immature DCs express on their cell surface four different cytotoxic TNF family ligands: TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis inducing ligand; while cancer cells express the corresponding death receptors. Disruptions of interactions between the four ligands expressed on DCs and corresponding death-signaling receptors expressed on cancer cells using specific Abs or R:Fc fusion proteins block the cytotoxic activity of DCs directed against cancer cells. The novel findings suggest that DC killing of cancer cells is mediated by the concerted engagement of four TNF family ligands of DCs with corresponding death receptors of cancer cells. Overall, our data demonstrate that DCs are fully equipped for an efficient direct apoptotic killing of cancer cells and suggest that this mechanism may play a critical role in both afferent and efferent anti-tumor immunity.
Lu
Ganwei
G
University of Pittsburgh Cancer Institute, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231, USA.
Janjic
Bratislav M
BM
Janjic
Jelena
J
Whiteside
Theresa L
TL
Storkus
Walter J
WJ
Vujanovic
Nikola L
NL
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000502:physiology; D053308:Lymphotoxin-beta; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D018613:Microscopy, Confocal; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505886:LTB protein, human; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha