title: Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines.
abstract: Since few leukemia-associated antigens (LAA) are characterized for acute myeloid leukemia (AML), apoptotic tumor cells constitute an attractive LAA source for DC-based vaccines, as they contain both characterized and unknown LAA. However, loading DC with apoptotic tumor cells may interfere with DC function. Previously, it was shown in mice that apoptotic blebs induce DC maturation, whereas apoptotic cell remnants (ACR) do not. Here, we analyzed human monocyte-derived DC (MoDC) functionality in vitro, after ingesting either allogeneic AML-derived ACR or blebs. We show that MoDC ingest blebs to a higher extent and are superior in migrating toward CCL19, as compared to ACR-loaded MoDC. Although MoDC cytokine production was unaffected, co-culturing bleb-loaded MoDC with T cells led to an increased T cell proliferation and IFNγ production. Moreover, antigen-specific CD8(+) T cells frequencies increased to 0.63 % by priming with bleb-loaded MoDC, compared to 0.16 % when primed with ACR-loaded MoDC. Importantly, CD8(+) T cells primed by bleb-loaded MoDC recognized their specific epitope at one to two orders of magnitude lower concentrations compared to ACR-loaded MoDC. In conclusion, superior ingestion efficiency and migration, combined with favorable T cell cytokine release and CD8(+) T cell priming ability and avidity, point to blebs as the preferred component of apoptotic leukemic cells for LAA loading of DC for the immunotherapy of AML.
authors.affiliation: Department of Hematology, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Jurjen M
authors.initials: JM
authors.lastname: Ruben
authors.forename: Willemijn
authors.initials: W
authors.lastname: van den Ancker
authors.forename: Hetty J
authors.initials: HJ
authors.lastname: Bontkes
authors.forename: Theresia M
authors.initials: TM
authors.lastname: Westers
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.forename: Arjan A
authors.initials: AA
authors.lastname: van de Loosdrecht
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000302:isolation & purification*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002465:Cell Movement; D055252:Cell-Derived Microparticles / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D018922:HL-60 Cells; D006801:Humans; D016130:Immunophenotyping; D059425:Interferon-gamma Release Tests; D015473:Leukemia, Promyelocytic, Acute / Q000276:immunology* / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D008942:Mitoxantrone / Q000627:therapeutic use; D009000:Monocytes / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D008942:Mitoxantrone