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

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 5 0.0085), RHAMM (p 5 0.03), WT1 (p 5 0.04) and Proteinase 3 (p 5 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 5 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.

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

“…Although it remains controversial whether allogeneic stem cell transplantation can alleviate the negative prognostic impact of adverse cytogenetics, it was recently demonstrated that leukemia stem cells, which are thought to account for relapse after therapy, highly express leukemiaassociated Ags and could be targeted by T cells. 22 Furthermore, leukemia-associated Ags-peptide specific T cells were detected in nearly all AML patients after allogeneic stem cell transplantation, supporting the concept of potential immunologic control of highrisk AML after aHCT. 23 Although higher patient age was not associated with shorter OS in our cohort, interestingly CR at the time of aHCT was not a positive factor for OS, although it was associated with a lower relapse rate in the univariate analysis.…”

Stratified computational meta-analysis of 2213 acute myeloid leukemia patients reveals age- and sex-dependent gene expression signatures

“…We used this approach to account for the lack within-study healthy controls in the curated gene expression datasets. To address this issue, we used 5 additional datasets the included within-study controls, GEO accessions: GSE107968, GSE68172 58 , GSE17054 59 , GSE33223 60 , and GSE15061 61 (Table 1B). We refer to the latter datasets hereafter as “covariate” reference datasets, as they were as the reference datasets in the batch correction.…”

Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases

“…Самые чув-ствительные системы для проведения полимеразной цепной реакции позволяли определять экспрессию PRAME у здоровых доноров. Однако активность гена у больных была выше как минимум на порядок [13][14][15][16][17].…”