Higher frequency of the CTLA‐4<sup>+</sup>LAG‐3<sup>+</sup> T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen, Youchun; Tan, Jiaxiong; Huang, Shuxin; Huang, Xin; Huang, Jingying; Chen, Jie; Yu, Zhi; Lu, Yuhong; Weng, Jianyu; Du, Xin; Li, Yangqiu; Zha, Xianfeng; Chen, Shaohua

doi:10.1111/ajco.13236

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…Although CTLA-4 plays a crucial role in prevention of autoimmunity, its activity can often contribute to evasion of anti-tumor immunity in cancer [ 70 ]. Upregulation of CTLA-4 was observed on T cell subsets of CML and AML patients [ 41 , 71 ]. Curiously, also leukemic cells from AML and CML patients can express CTLA-4 [ 72 ].…”

Section: Leukemia-derived Factors That Promote Immune Evasionmentioning

confidence: 99%

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Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.

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Section: Leukemia-derived Factors That Promote Immune Evasionmentioning

confidence: 99%

“…It is suggested that tumor cells express MHC-II to bind with LAG-3 and inhibit TCR signaling on effector T cells. As LAG-3 is overexpressed on T cells in CML and AML patients [ 71 , 81 ], it could be yet another way to evade immune response by leukemic cells [ 98 ].…”

Section: Leukemia-derived Factors That Promote Immune Evasionmentioning

confidence: 99%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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“…In addition, cancer cells and AML cells are able to escape the host immune surveillance by inactivating cytotoxic T cells (CTLs) [18]. It has been demonstrated that T cell immune inhibitory receptors, also known as immune checkpoint receptors, such as program death-1 (PD-1), T cell immunoglobulin mucin 3 (Tim-3), cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) and T cell lymphocyte activation gene-3 (LAG-3) have increased expression in T cells in patients with newly diagnosed and relapsed AML and murine AML models [19][20][21][22]. For example, leukemia progression resulted in increased regulatory T (Treg) cells and PD-1 ligand (PD-L1) + CD8+ T cells at tumor sites in a mouse AML model, and PD-L1 inhibitor treatment could restore the proliferation and cytotoxic function of T cells at tumor sites, reduce AML tumor burden, and increase overall survival [23,24].…”

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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“…1a, b). We further analyzed the expression patterns of PD-1, PD-L1, and PD-L2 with other important ICs [7][8][9]. Subsequently, with Pearson's correlation analysis, we found that the expression of PD-1, PD-L1, or PD-L2 was positively associated with the expression of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (r = 0.259, P < 0.001; r = 0.435, P < 0.001; r = 0.269, P < 0.001, respectively) and lymphocyte activation gene-3 (LAG-3) (r = 0.275, P < 0.001; r = 0.276, P < 0.001; r = 0.160, P = 0.033, respectively) in the TCGA group (Fig.…”

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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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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Cited by 24 publications

References 46 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

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

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Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Cited by 24 publications

References 46 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

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

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia