Release of iC3b from apoptotic tumor cells induces tolerance by binding to immature dendritic cells in vitro and in vivo |
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Authors: | Jan Schmidt Christoph Klempp Markus W Büchler Angela Märten |
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Institution: | (1) Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany |
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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. |
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Keywords: | iC3b Apoptosis Tolerance Dendritic cells |
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