Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens.
Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. We investigated the role of cytotoxic T-lymphocytes (CTL) counteracting and recognizing LSC. Leukemia-associated antigens (LAA) represent immunogenic structures to target LSC. We enriched the LSC-containing fraction of 20 AML patients and hematopoietic stem cells (HSC) of healthy volunteers. Using microarray analysis and qRT-PCR we detected high expression of several LAA in AML cells but also in LSC. PRAME (p = 0.0085), RHAMM (p = 0.03), WT1 (p = 0.04) and Proteinase 3 (p = 0.04) showed significant differential expression in LSC compared with HSC. PRAME, RHAMM and WT1 are furthermore also lower expressed on leukemic bulk. In contrast, Proteinase 3 indicates a higher expression on leukemic bulk than on LSC. In colony forming unit (CFU) immunoassays, T cells stimulated against various LAA indicated a significant inhibition of CFUs in AML patient samples. The LAA PRAME, RHAMM and WT1 showed highest immunogenic responses with a range up to 58-83%. In a proof of principle xenotransplant mouse model, PRAME-stimulated CTL targeted AML stem cells, reflected by a delayed engraftment of leukemia (p = 0.0159). Taken together, we demonstrated the expression of several LAA in LSC. LAA-specific T cells are able to hamper LSC in immunoassays and in a mouse model, which suggests that immunotherapeutic approaches have the potential to target malignant stem cells.
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Vanessa
V
Schneider
Department of Internal Medicine III, University of Ulm, Ulm, Germany.|Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lu
L
Zhang
Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donor Service Baden-Württemberg - Hessia, Germany.
Markus
M
Rojewski
Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donor Service Baden-Württemberg - Hessia, Germany.
Natalie
N
Fekete
Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donor Service Baden-Württemberg - Hessia, Germany.
Hubert
H
Schrezenmeier
Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donor Service Baden-Württemberg - Hessia, Germany.
Alexander
A
Erle
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Lars
L
Bullinger
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Susanne
S
Hofmann
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Marlies
M
Götz
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Konstanze
K
Döhner
Institute of Experimental Cancer Research & Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Susann
S
Ihme
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Hartmut
H
Döhner
Institute of Experimental Cancer Research & Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Christian
C
Buske
Institute of Experimental Cancer Research & Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Michaela
M
Feuring-Buske
Department of Internal Medicine III, University of Ulm, Ulm, Germany.|Department of Internal Medicine, Diakonie Hospital Stuttgart, Stuttgart, Germany.
Jochen
J
Greiner
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm
AML; cytotoxic T cells; leukemia associated antigens; leukemic stem cells; therapeutic targets