Human dendritic cells induce tumor-specific apoptosis by soluble factors.
Dendritic cells (DCs) are the most potent antigen producing cells (APCs) for initiation of immune responses including anti-tumor immune responses. In previous reports, it has been shown that DCs efficiently take up and process apoptotic or necrotic bodies of tumor cells. It has also been shown that DCs pulsed with tumor cell apoptotic bodies, lysates or peptides generate potent anti-tumor immune responses. Direct interactions between DCs and viable tumor cells, however, have not been clearly elucidated. We report that monocyte-derived, CD1a+ immature DCs (iDCs) significantly inhibit the growth of breast tumor cells in coculture and transwell experiments in the presence of soluble CD40 ligand (sCD40L), LPS or both. The growth inhibition effects correlated with cell cycle arrest and apoptosis of breast tumor cells. The effects were associated with morphological changes of tumor cells from a round shape to a flat, spindle shape. In contrast, no inhibition of proliferation or morphological changes was observed on normal PBMC, K562 or breast fibroblasts. Interestingly, iDCs undergoing maturation induced by sCD40L+LPS induced a much stronger growth inhibitory effect than iDCs alone or mature DCs treated with sCD40L+LPS. Fractionation of supernatants showed the anti-tumor effects were mediated by a TNF-alpha-dependent and -independent mechanism. Soluble FasL and TRAIL were not involved. Our findings suggest that maturing DCs have the intrinsic ability to induce cell-cycle arrest and apoptosis of breast tumor cells through soluble factors, but not normal cells, in addition to their Ag presentation function.
D017304:Annexin A5 / Q000378:metabolism; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism; D009336:Necrosis; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; D019013:CD40 Antigens; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand