- Letter to the Editor
- Open Access
Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia
Journal of Hematology & Oncology volume 11, Article number: 93 (2018)
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.
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.
The percentages of the TSCM, TCM, TEM, and TEF cells in the CD4+ and CD8+ populations were analyzed in 20 cases with AML (17 cases in newly diagnosed and 3 cases with AML relapse) (Fig. 1a, d) [8, 9]. The CD8+ TSCM and CD8+ TCM cells significantly decreased in the PB of these patients (Fig. 1e, g), whereas there was no significant change in the CD4+ population (Fig. 1b, g). Thus, the changes in the memory T cell subsets appeared to mainly involve CD8+ T cells. The shift from TSCM and TCM cells to a higher ratio of differentiated TEM and TEF cells is thought to be due to the constant exposure of T cells to AML cells and the leukemia environment, leading to T cell exhaustion and/or dysfunction .
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.
Next, we compared the distribution of memory T cells in AML patients younger (AMLy) and older (AMLo) than 60 years . Unlike healthy individuals (HIs), the memory T cell subset distribution in the AMLy cohort was strikingly different than that in younger HIs (HIy) and tended to have a similar distribution pattern as that detected in the HIo and AMLo groups with a more obvious difference in the CD8+ population (Figs. 1g and 2a, b). These findings indicate that the leukemia microenvironment might drive T cell differentiation in AMLy. Whether such a skewed T cell distribution in AMLy truly represents T cell senescence remains an open question ; however, T cells in AMLo patients may not be able to further differentiate due to inherent T cell senescence, which may be an immune factor underlying the inferior prognosis of AMLo patients. Together, these data may suggest that T cell exhaustion and senescence are involved in T cell immune impairment, leading to an inefficient anti-tumor response.
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.
Acute myeloid leukemia
Chronic myeloid leukemia
Hematopoietic stem cell transplantation
Peripheral blood mononuclear cells
- TCM :
Central memory T cells
- TEF :
Terminal effector T cells
- TEM :
Effector memory T cells
- TSCM :
Stem cell memory T cells
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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).
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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This study was approved by the ethics committee of The First Affiliated Hospital of Jinan University.
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Xu, L., Yao, D., Tan, J. et al. Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia. J Hematol Oncol 11, 93 (2018). https://doi.org/10.1186/s13045-018-0636-y
- Stem cell memory T cells
- Central memory T cells
- Effector memory T cells
- CD8+ T cells
- Acute myeloid leukemia
- Bone marrow
- Peripheral blood