title: Immature dendritic cells kill ovarian carcinoma cells by a FAS/FASL pathway, enabling them to sensitize tumor-specific CTLs.
abstract: Dendritic cells (DCs) can acquire antigen(s) from apoptotic tumor cells, resulting in an immunogen that can induce class I-restricted cytotoxic T lymphocytes (CTLs) and protective tumor rejection. Here, we investigated whether DCs derived from ascitic monocytes of patients with ovarian carcinoma could kill autologous ovarian tumor cells and if as a result they would acquire antigen(s) enabling them to induce a tumor-specific immunity. We found that the immature DCs could exert a significant cytotoxicity towards autologous and allogeneic ovarian tumor cells. This cytotoxicity was independent of Ca(2+) and could be inhibited by anti-Fas IgG1 monoclonal antibody, indicating the involvement of the Fas/Fas ligand (FasL) pathway in the cytotoxic mechanism. Further supporting this conclusion, the ascitic monocyte-derived DCs expressed high levels of FasL mRNA and intracellular FasL and significant levels of Fas were also revealed on the surface of ovarian tumor cells. Coculture of DCs induced apoptosis in ovarian carcinoma cells, as well as uptake of apoptotic tumor cells into the cytoplasma of the DCs, as visualized by immunofluoresence. Autologous DCs cocultured with apoptotic ovarian tumor cells were able to specifically stimulate tumor-specific CTLs, whereas DCs cocultured with necrotic ovarian cells were unable to do so. Collectively, these results demonstrate that immature DCs can kill autologous ovarian carcinoma cells via the Ca(2+)-independent Fas/FasL pathway and that this may have important consequences for their ability to stimulate tumor-specific CTLs.
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden. ryang@mail.jhmi.edu
authors.forename: R
authors.initials: R
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Gruber
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D001201:Ascites / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D002118:Calcium