A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

Huang, Jingying; Tan, Jiaxiong; Chen, Youchun; Huang, Shuxin; Xu, Ling; Zhang, Yikai; Lu, Yuhong; Yu, Zhi; Chen, Shaohua; Li, Yangqiu

doi:10.1002/jlb.ma0119-021r

Cited by 30 publications

(30 citation statements)

References 41 publications

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“…With the recent development of targeted and immunotherapy, a number of ongoing studies aim to produce novel AML therapies, including conventional cytotoxic chemotherapies, genetic and epigenetic targeted therapies, and immunotherapies [3][4][5][6]. The T cell immune status of patients is an important factor related to the prognosis of leukemia [7][8][9][10][11]. Significantly, improvement in the clinical outcome of hematological malignancies was demonstrated by using immunotherapies such as CAR-T cell transfusion [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Tan

Huang

et al. 2020

Biomark Res

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Background: Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. We found higher numbers of programmed death-1 (PD-1) + exhausted T cells in peripheral blood (PB) from acute myeloid leukemia (AML) patients. To investigate the leukemic BM influence on immunosuppression, we further compared the distributions of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) and the exhausted T cell phenotype in PB and BM from AML patients and characterized their relationship with clinical outcome. Methods: PB and BM samples from 15 patients with newly diagnosed AML were collected and analyzed for the expression of PD-1, Tim-3, CD244, and CD57 on CD3+, CD4+, and CD8+ T cells by multicolor flow cytometry. Results: The proportions of PD-1 + CD3+ and PD-1 + CD8+ T cells were significantly higher in BM compared with PB. Similarly, higher PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in BM, and an increased tendency for PD-1 + CD244 + CD4+ T cells was also detected in this group. In contrast, increased Tim-3 + CD4+/ Tim-3 + CD244 + CD4+ T cells were predominant in BM compared with PB, but there was no statistically significant difference in Tim-3 + CD8+ T cells. Moreover, PD-1 and Tim-3 double-positive CD3+/CD4+/CD8+ T cells were significantly increased in the BM group. In addition, a higher proportion of PD-1 + Tim-3 + CD3+ T cells in the BM and PD-1 + Tim-3 + CD4+ T cells in PB was detected in non-complete remission (NCR) compared with complete remission (CR) patients after first-cycle chemotherapy. Conclusions: Upregulation of PD-1 and Tim-3 and the exhausted phenotype of CD4+ and CD8+ T cells in the BM of AML patients may contribute to mediating the leukemic immunosuppressive microenvironment, and increased PD-1 + Tim-3+ CD8+ T cells may be related to T cell dysfunction in AML, which may influence clinical outcome.

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Section: Introductionmentioning

confidence: 99%

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Tan

Huang

et al. 2020

Biomark Res

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“…To the Editor, Immune checkpoint (IC) blockade by inhibitors of the programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has significantly improved clinical outcome for a variety of solid tumors [1,2], while little is known about the role of ICs in leukemia [3]. Previous reports have shown that higher numbers of PD-1 + T cells are related to poor outcome for patients with acute myeloid leukemia (AML) [3]. Clinical trials using PD-1 inhibitors are ongoing to treat patients with a high risk for AML relapse [4].…”

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confidence: 99%

Expression patterns of immune checkpoints in acute myeloid leukemia

et al. 2020

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Immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival. This type of therapy is still not available for acute myeloid leukemia (AML). One major issue is the lack of knowledge for the expression patterns of immune checkpoints (IC) in AML. In this study, we first explored the prognostic value of ICs for AML patients by analyzing RNA-seq and mutation data from 176 AML patients from the Cancer Genome Atlas (TCGA) database. We further validated the results of the database analysis by analyzing bone marrow (BM) samples from 62 patients with de novo AML. Both TCGA data and validation results indicated that high expression of PD-1, PD-L1, and PD-L2 was associated with poor overall survival (OS) in AML patients. In addition, increased co-expression of PD-1/CTLA-4 or PD-L2/CTLA-4 correlated with poor OS in AML patients (3-year OS: TGCA data 30% vs 0% and 20% vs 0%, validation group 57% vs 31% and 57% vs 33%, respectively) (P < 0.05).

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“…It is well known that M3 is a prognostically favorable subtype of AML. Previous studies have shown fewer defects in T cell proliferation and activation in M3 compared with other AML subtypes . Therefore, we tried to compare the distribution of Tim‐3 in T cells from different AML subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing data have shown that upregulation of immune inhibitory receptors also called as immune checkpoints, such as programmed cell death receptor‐1 (PD‐1), cytotoxic T lymphocyte‐associated molecule‐4 (CTLA‐4), T cell immunoglobulin mucin‐domain‐containing‐3 (Tim‐3), T cell lymphocyte activation gene‐3, and B and T lymphocyte attenuator, which can reduce T cell activation and promote T cell exhaustion, is the primary reason for cancer immunosuppression . Checkpoint inhibitor‐based immunotherapy, such as anti‐PD‐1, CTLA‐4, and programmed cell death ligand‐1 antibodies, has proved as novel and powerful therapy against solid tumors, such as lung cancer and improving overall survival .…”

Section: Introductionmentioning

confidence: 99%

“…This may be due to the complexity of the leukemic bone marrow (BM) microenvironment in which persistent stimulation of leukemia cell‐derived antigen results in more complex T cell exhaustion and dysfunction . The heterogeneity of exhausted T cells may be a reason for the lower effects of PD‐1 inhibitor . In this case, more than one immune checkpoint receptors may contribute to overcoming the T cell dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Increasing Tim‐3+CD244+, Tim‐3+CD57+, and Tim‐3+PD‐1+ T cells in patients with acute myeloid leukemia

Tan

Huang

et al. 2020

Asia-Pac J Clncl Oncology

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Aim:To characterize the distribution of T cell immunoglobulin mucin-domain-containing-3 (Tim-3) within the exhausted T cells in patients with newly diagnosed acute myeloid leukemia (AML) and AML in complete remission. Methods:Tim-3 expression and coexpression with PD-1, CD244, and CD57 in CD3+, CD4+, and CD8+T cells were analyzed by multicolored fluorescent flow cytometry in peripheral blood from 28 newly diagnosed, untreated AML patient and 12 cases with AML in complete remission, 23 healthy individuals served as control.Results: Increasing Tim-3+CD244+ and Tim-3+CD57+ in CD3+, CD4+, and CD8+ T cells were found in AML and AML-CR groups in comparison with healthy controls. Similarly, increasing Tim-3 coexpression PD-1+ CD3+/CD4+/CD8+ T cells were found in AML group. A high tendency of PD-1+Tim-3+CD3+/CD4+/CD8+ T cells was detected in the AML-M4 subtype group followed by the M2 group, and a low tendency was found in the M3 group. Moreover, Tim-3+CD244+CD8+ T cells were found to be significantly higher in the M4 than that in M3 group. Dynamic changes of Tim-3+ T cells in AML patients who achieved CR after chemotherapy at different time points showed that Tim-3+ T cell subsets were evidently decreased; however, they remained at a higher level in most AML-CR patients.

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A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

Cited by 30 publications

References 41 publications

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Expression patterns of immune checkpoints in acute myeloid leukemia

Increasing Tim‐3+CD244+, Tim‐3+CD57+, and Tim‐3+PD‐1+ T cells in patients with acute myeloid leukemia

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