title: Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses.
abstract: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the majority of patients initially respond to upfront chemotherapy, relapses with poor prognosis occur in approximately 20% of cases. Thus, novel therapeutic strategies are required to improve long-term survival. B-cell precursor (BCP)-ALL cells express low levels of immunogenic molecules and, therefore, are poorly recognized by the immune system. In the present study, we investigated the effect of various combinations of potent B-cell stimulators including CpG, Interleukin (IL)-2 family cytokines and CD40 ligand (CD40L) on the immunogenicity of primary BCP-ALL cells and a series of BCP-ALL cell lines. The combination of CpG, IL-4 and CD40L was identified as most effective to enhance expression of immunogenic molecules on BCP-ALL cells, resulting in an increased capacity to induce both allogeneic and autologous cytotoxic T lymphocytes (CTL). Importantly, such CTL exhibited significant anti-leukemic cytotoxicity not only towards treated, but also towards untreated BCP-ALL cells. Our results demonstrate that the combination of CpG with other B-cell stimulators is more efficient than CpG alone in generating immunogenic BCP-ALL cells and anti-leukemic CTL. Our results may stimulate the development of novel adoptive T cell transfer approaches for the management of BCP-ALL.
authors.affiliation: Department of Pediatrics, University of Ulm, Ulm, Germany. dorit.fabricius@uni-ulm.de
authors.forename: D
authors.initials: D
authors.lastname: Fabricius
authors.forename: L
authors.initials: L
authors.lastname: Breckerbohm
authors.forename: A
authors.initials: A
authors.lastname: Vollmer
authors.forename: M
authors.initials: M
authors.lastname: Queudeville
authors.forename: S M
authors.initials: SM
authors.lastname: Eckhoff
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.forename: G
authors.initials: G
authors.lastname: Strauss
authors.forename: K-M
authors.initials: KM
authors.lastname: Debatin
authors.forename: B
authors.initials: B
authors.lastname: Jahrsdörfer
authors.forename: L H
authors.initials: LH
authors.lastname: Meyer
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D023201:CD40 Ligand / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000276:immunology; D002648:Child; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016219:Immunotherapy, Adoptive; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; C508598:IL4 protein, human; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D023201:CD40 Ligand; D015847:Interleukin-4