title: Exposure of CD34+ precursors to cytostatic anthraquinone-derivatives induces rapid dendritic cell differentiation: implications for cancer immunotherapy.
abstract: Appropriate activation of dendritic cells (DC) is essential for successful active vaccination and induction of cell-mediated immunity. The scarcity of precursor cells, as well as long culture methods, have hampered wide-scale application of DC vaccines derived from CD34(+) precursors, despite their suggested superior efficacy over the more commonly applied monocyte-derived DC (MoDC). Here, employing the CD34(+)/CD14(+) AML-derived human DC progenitor cell line MUTZ3, we show that cytostatic anthraquinone-derivatives (i.e., the anthracenedione mitoxantrone and the related anthracyclin doxorubicin) induce rapid differentiation of CD34(+) DC precursors into functional antigen-presenting cells (APC) in a three-day protocol. The drugs were found to act specifically on CD34(+), and not on CD14(+) DC precursors. Importantly, these observations were confirmed for primary CD34(+) and CD14(+) DC precursors from peripheral blood. Mitoxantrone-generated DC were fully differentiated within three days and after an additional 24 h of maturation, were as capable as standard 9-day differentiated and matured DC to migrate toward the lymph node-homing chemokines CCL19 and CCL21, to induce primary allogeneic T cell proliferation, and to prime functional MART1-specific CD8(+) T lymphocytes. Our finding that anthraquinone-derivatives like mitoxantrone support rapid high-efficiency differentiation of DC precursors may have consequences for in vitro production of DC vaccines as well as for novel immunochemotherapy strategies.
authors.affiliation: Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|Division of Immunotherapy, Medical Oncology Laboratory, VU University Medical Center, de Boelelaan 1117-CCA 2.44, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Rieneke
authors.initials: R
authors.lastname: van de Ven
authors.affiliation: Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|DCPrime B.V, De Boelelaan 1085 (W&N), 1081 HV, Amsterdam, The Netherlands.
authors.forename: Anneke W
authors.initials: AW
authors.lastname: Reurs
authors.affiliation: Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|DCPrime B.V, De Boelelaan 1085 (W&N), 1081 HV, Amsterdam, The Netherlands.
authors.forename: Pepijn G J T B
authors.initials: PGJTB
authors.lastname: Wijnands
authors.affiliation: DCPrime B.V, De Boelelaan 1085 (W&N), 1081 HV, Amsterdam, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: van Wetering
authors.affiliation: DCPrime B.V, De Boelelaan 1085 (W&N), 1081 HV, Amsterdam, The Netherlands.
authors.forename: Ada M
authors.initials: AM
authors.lastname: Kruisbeek
authors.affiliation: Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.affiliation: Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.affiliation: Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|DCPrime B.V, De Boelelaan 1085 (W&N), 1081 HV, Amsterdam, The Netherlands.
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.affiliation: Division of Immunotherapy, Medical Oncology Laboratory, VU University Medical Center, de Boelelaan 1117-CCA 2.44, 1081 HV, Amsterdam, The Netherlands. td.degruijl@vumc.nl.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology; D000880:Anthraquinones / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D019496:Cancer Vaccines; D002454:Cell Differentiation; D002460:Cell Line; D054415:Chemokine CCL19 / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism; D054697:Cytostatic Agents / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy
chemical_list: D018943:Anthracyclines; D000880:Anthraquinones; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054697:Cytostatic Agents; D018950:Lipopolysaccharide Receptors