Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens

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Item Type:	Article
Title:	Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens
Creators Name:	Schneider, V., Zhang, L., Rojewski, M., Fekete, N., Schrezenmeier, H., Erle, A., Bullinger, L., Hofmann, S., Götz, M., Döhner, K., Ihme, S., Döhner, H., Buske, C., Feuring-Buske, M. and Greiner, J.
Abstract:	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.
Keywords:	Leukemic Stem Cells, Leukemia Associated Antigens, Therapeutic Targets, AML, Cytotoxic T Cells, Animals, Mice
Source:	International Journal of Cancer
ISSN:	0020-7136
Publisher:	Wiley
Volume:	137
Number:	9
Page Range:	2083-2092
Date:	1 November 2015
Official Publication:	https://doi.org/10.1002/ijc.29583
PubMed:	View item in PubMed

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