title: Chronic myeloid leukemia cells express tumor-associated antigens eliciting specific CD8+ T-cell responses and are lacking costimulatory molecules.
abstract: Specific immunotherapies for patients with chronic myeloid leukemia (CML) might eliminate residual CML cells after therapy with imatinib or chemotherapy and might enhance a specific graft-versus-leukemia effect after allogeneic stem cell transplantation. Here, we investigated the mRNA expression and T-cell recognition of tumor-associated antigens or leukemia-associated antigens (LAAs) in 34 patients with CML. Several LAAs are expressed in CML and therefore are candidate structures for specific immunotherapies: bcr-abl (100%), G250 (24%), hTERT (53%), MPP11 (91%), NEWREN60 (94%), PRAME (62%), Proteinase3 (71%), RHAMM/CD168 (83%), and WT1 (53%), but not BAGE, MAGE-A1, SSX2, or NY-ESO-1. The frequency of mRNA expression of RHAMM/CD168, Proteinase3, and PRAME was higher in acceleration phase and blast crisis. In flow cytometry, CD34+ progenitor cells typed positive for HLA molecules but were deficient for CD40, CD80, CD83, and CD86. However, RHAMM/CD168 R3-peptide (ILSLELMKL)-specific T-cell responses in CML patients were demonstrated by ELISPOT analysis and specific lysis of RHAMM/CD168 R3-pulsed T2 cells and CD34+ CML cells in chromium-51 release assays. RHAMM-R3-specific T cells could be phenotyped as CD8+R3*tetramer+CD45RA+CCR7-CD27- early effector T cells by tetramer staining. Therefore, vaccination strategies inducing such RHAMM-R3-directed effector T cells might be a promising approach to enhance specific immune responses against CML cells.
authors.affiliation: 3rd Department of Internal Medicine, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Giannopoulos
authors.forename: Jinfei
authors.initials: J
authors.lastname: Chen
authors.forename: Christian
authors.initials: C
authors.lastname: Brunner
authors.forename: Thomas
authors.initials: T
authors.lastname: Barth
authors.forename: Anita
authors.initials: A
authors.lastname: Schmitt
authors.forename: Markus
authors.initials: M
authors.lastname: Wiesneth
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Jochen
authors.initials: J
authors.lastname: Greiner
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D016130:Immunophenotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; C098946:hyaluronan-mediated motility receptor; D016044:Fusion Proteins, bcr-abl