Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia
Stem cell memory T (TSCM) and central memory T (TCM) cells can rapidly differentiate into effector memory (TEM) and terminal effector (TEF) T cells, and have the most potential for immunotherapy. In this study, we found that the frequency of TSCM and TCM cells in the CD8+ population dramatically decreased together with increases in TEM and TEF cells, particularly in younger patients with acute myeloid leukemia (AML) (< 60 years). These alterations persisted in patients who achieved complete remission after chemotherapy. The decrease in TSCM and TCM together with the increase in differentiated TEM and TEF subsets in CD8+ T cells may explain the reduced T cell response and subdued anti-leukemia capacity in AML patients.
KeywordsStem cell memory T cells Central memory T cells Effector memory T cells CD8+ T cells Acute myeloid leukemia Bone marrow Peripheral blood
Acute myeloid leukemia
Chronic myeloid leukemia
Hematopoietic stem cell transplantation
Peripheral blood mononuclear cells
Central memory T cells
Terminal effector T cells
Effector memory T cells
Stem cell memory T cells
To the editor
Clinical applications of immunotherapy for AML lag behind those for solid tumors and lymphocytic leukemia [1, 2, 3]. Recently, a new memory T cell subset, stem cell memory T (TSCM), which has stem cell-like capacity, has been discovered [4, 5, 6]. However, little is known about the role of these cells in AML. In this study, we assessed the distribution of CD4+ and CD8+ TSCM, central memory T (TCM), T effector memory (TEM), and T terminal effector (TEF) cells in peripheral blood (PB) and bone marrow (BM) from patients with AML and those with AML in complete remission (AML-CR) by multicolor flow cytometry. The gating strategy used in this study followed a published protocol . The CD4+ and CD8+ T cells were divided into four subgroups according to the CCR7 and CD45RO expression pattern: naïve and TSCM cells (CCR7+CD45RO−), TCM cells (CCR7+CD45RO+), TEM cells (CCR7−CD45RO+), and TEF cells (CCR7−CD45RO−). The TSCM population was defined by double positive CD95 and CD28 expression.
To study the influence of the tumor microenvironment on the memory T cell distribution and function in leukemia patients, we collected seven pairs of PB and BM samples from AML patients at the time of diagnosis and compared the distributions of memory T cell subsets. The differences in each subset appeared to vary widely (Fig. 1c, f). A low percentage of CD4+ TCM cells and a corresponding high percentage of CD4+ TEM and TEF cells were observed in the BM compared with PB (Fig. 1c). In the CD8+ population, the changes appeared to be specific to each individual, and lower CD8+ TSCM and CD8+ TCM percentages were observed in the BM in half of the patients, whereas there were high percentages of CD8+ TSCM and CD8+ TCM cells in the BM compared with PB in the remaining samples. It has been reported that T cells in normal BM mainly possess a memory phenotype, particularly for CD8+ TCM cells , suggesting that alterations in the leukemic BM niche in different AML individuals and AML subtypes may have different impact on TCM homing.
We next compared differences in the distribution of memory T cell subsets between the AMLy, AML-CR, and HIy groups. A persistent, skewed memory T cell distribution was demonstrated for AML patients who achieved CR after chemotherapy (Fig. 2c, d). CD4+ and CD8+ TSCM cells were predominantly increased at different time points after CR, while the change in other memory T cell subsets was relatively different (Fig. 2e, f). Overall, with the exception of incomplete recovery of the TSCM cells, the reduction in TCM cells and corresponding excessive accumulation of TEM and TEF cells were more evident in AML patients with CR (Fig. 1g), which may be related to the immune suppression of chemotherapy.
We want to thank the flow facility of the Biological Translational Research Institute of Jinan University as well as Yanqiong Jia, a research assistant from the Translational Research Institute of Jinan University. We also would like to thank the volunteers who donated blood for this project.
This study was supported by grants from the National Natural Science Foundation of China (Nos. 91642111, 81770152, and 81570143), the Guangdong Provincial Basic Research Program (No. 2015B020227003), the Guangdong Provincial Applied Science and Technology Research & Development Program (No. 2016B020237006), the Guangzhou Science and Technology Project (Nos. 201510010211, 201807010004, and 201803040017), and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (No. pdjh2017b0065).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
YQL contributed to the concept development and study design. LX coordinated the study. LX, DLY, JXT, ZFH, SHL, XFZ, and SHC performed the laboratory studies. ZY, JC, GXL, CLW, and FFZ collected the clinical data. DLY contributed to figure preparation. YQL, XL, and DLY drafted the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the ethics committee of The First Affiliated Hospital of Jinan University.
Consent for publication
The authors declare that they have no competing interests.
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