Abstract
BackgroundNon-traditional CD4+CD25–CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT).MethodsThe frequency of CD4+CD25–CD69+ T cells among the CD4+ T cell population from the bone marrow of relapsed patients, patients with positive minimal residual disease (MRD+) and healthy donors was examined by flow cytometry. The CD4+CD25-CD69+ T cells were also stained with the intracellular markers to determine the cytokine (TGF-β, IL-2 and IL-10) secretion.ResultsThe results showed that the frequency of CD4+CD25–CD69 + T cells was markedly increased in patients in the relapsed group and the MRD + group compared to the healthy donor group. The percentage of this subset of T cells was significantly decreased after effective intervention treatment. We also analyzed the reconstitution of CD4+CD25–CD69+ T cells at various time points after allo-HSCT, and the results showed that this subset of T cells reconstituted rapidly and reached a relatively higher level at +60 d in patients compared to controls. The incidence of either MRD+ or relapse in patients with a high frequency of CD4+CD25-CD69+ T cells (>7%) was significantly higher than that of patients with a low frequency of CD4+CD25-CD69+ T cells at +60 d, +90 d and +270 d after transplant. However, our preliminary data indicated that CD4+CD25-CD69+ T cells may not exert immunoregulatory function via cytokine secretion.ConclusionsThis study provides the first clinical evidence of a correlation between non-traditional CD4+CD25-CD69+ Tregs and leukemia relapse after allo-HSCT and suggests that exploration of new methods of adoptive immunotherapy may be beneficial. Further research related to regulatory mechanism behind this phenomenon would be necessary.
Highlights
Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for patients with hematological malignancies, leukemia relapse remains one of the most common causes of treatment failure after transplant
Higher frequency of CD4+CD25-CD69+ T cells in the bone marrow of MRD + and relapsed patients To investigate the relationship between CD4+CD25CD69+ T cells and leukemia relapse, we first examined the frequency of these cells in the bone marrow from 29 patients who were treated for a malignant hematological disease with allo-HSCT, including patients undergoing hematological relapse (n = 22) and those with a positive MRD status (n = 7)
The frequency of CD4+CD25-CD69+ T cells in the bone marrow from the healthy donors was 2.79%; the frequency of this subset was significantly increased in patients with detectable MRD (7.60%, range, 4.53-9.14%, P = 0.008) and those undergoing hematological relapse (12.96%, range, 8.62-20.49%, P < 0.001) compared to the control group
Summary
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative procedure for patients with hematological malignancies, leukemia relapse remains one of the most common causes of treatment failure after transplant. Allo-HSCT can be considered a type of immunotherapy directed toward malignant hematologic diseases or the graft-versusleukemia (GVL) effect due to either infused immunocytes in the graft or reconstituted T cells after transplant. Several studies have demonstrated that the presence of Tregs in either the tumor microenvironment or circulation might be involved in immune escape mechanisms and the failure of the host to trigger an efficient immunological antitumor response [8,9,10]. Non-traditional CD4+CD25–CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT)
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