title: Release of iC3b from apoptotic tumor cells induces tolerance by binding to immature dendritic cells in vitro and in vivo.
abstract: Chemo- as well as immunotherapeutical approaches induce apoptosis in tumor cells. Apoptotic cells are known to activate homologous complement and to be opsonized with iC3b. Since maturation of dendritic cells (DC) can be inhibited by binding of iC3b to the complement receptor 3 (CR3, CD11b/CD18) and because immature DC induce tolerance, we investigated the induction of tolerance after pulsing DC with apoptotic cells in the presence or absence of native serum. Apoptosis in pancreatic carcinoma cells was induced either by heat-stress, chemotherapy or anti-Her2 antibody. Monocyte-derived DC were pulsed with apoptotic cells with or without native serum. DC were analyzed for the maturation state by flow cytometry and the cytotoxic activity was determined. Tolerance was prevented by addition of substances such as anti CD11b or N-acetyl-D-Glucosamine (NADG) which block iC3b binding to CR3. Furthermore, binding of iC3b from apoptotic cells to DC was blocked in a syngeneic pancreatic carcinoma mouse model. All of the former strategies for apoptosis induction resulted in iC3b release. Pulsing DC with apoptotic cells in the presence of serum prevents maturation of DC and induces finally tolerance. This tolerance could be prevented almost completely by blocking the interaction of iC3b with the CR3 receptor. This could be shown as well in an immunocompetent mouse model. Chemo- as well as immunotherapeutical approaches induce apoptosis in tumor cells. Release of iC3b from apoptotic tumor cells prevents fully maturation of DC and immature DC induce antigen-specific silencing or tolerance. Blocking of iC3b-binding could mostly prevent this effect.
authors.affiliation: Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.forename: Christoph
authors.initials: C
authors.lastname: Klempp
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Angela
authors.initials: A
authors.lastname: Märten
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D001665:Binding Sites; D002277:Carcinoma / Q000473:pathology*; D002454:Cell Differentiation; D003179:Complement C3b / Q000378:metabolism*; D003713:Dendritic Cells; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007121:Immunocompetence; D008213:Lymphocyte Activation; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology*; D044967:Serum; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D003179:Complement C3b