<scp>Chronic myeloid leukaemia</scp> patients at diagnosis and resistant to tyrosine kinase inhibitor therapy display exhausted T‐cell phenotype

Harrington, Patrick; Dillon, Richard; Radia, Deepti; McLornan, Donal P.; Woodley, Claire; Asirvatham, Susan; Raj, Kavita; Garcia, Natalia Curto; Saunders, Jamie; Kordasti, Shahram; Harrison, Claire; Lavallade, Hugues de

doi:10.1111/bjh.18302

Cited by 7 publications

(11 citation statements)

References 24 publications

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“…On the level of the total CD4 + and CD8 + population, we only found a few function markers or even no markers were changed in the PB and BM of patients respectively, however, further analysis of the T cell subsets revealed that the markers representing the activation and proliferation (CD38, HLA-DR, and CD69) (31,32) were decreased in the less differentiated T N and T CM subsets in the DN-CML and TKI-F patients, while gradually recovered in the pre-MMR and MMR patients. In addition, the higher expression of PD-1 on peripheral CD8 + T cells detected in all the patients treated with TKI, especially for TKI-F patients, this consistent with recent research that a higher percentage of PD-1 detected on CD4 + , CD8 + and Treg cells in CML patients resistant to TKI (33), however, on the level of T cell subsets, we can see that the percentage of PD-1 high expression T cell subsets mainly decreased in the patients who achieved MMR but not in TKI-F and Pre-MMR patients. Those results indicated that dynamic monitoring of the changes of these immune phenotypes in the level of T cell subsets may help to predict the effects and outcomes after TKI treatment.…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, previous studies have found that CD80 may prefer to combine with PD-L1 and CTLA-4 if CD80 had an advantage in expression ( 42 ). Several studies have found that CTLA4 expression regulatory T cells accumulated in the leukemia environment of DN-CML patients, while CML cells increased the expression of PD-L1 ( 18 , 33 , 43 ). Therefore, though the expression of CD28 + T cells remains at a normal level, the decreased level of CD86 + DCs and the unbalanced ratio of CD80/CD86 may also prevent the activation of T cells in DN-CML patients.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive analysis of the immune pattern of T cell subsets in chronic myeloid leukemia before and after TKI treatment

Yao

Lai

et al. 2023

Front. Immunol.

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BackgroundImmunological phenotypes and differentiation statuses commonly decide the T cell function and anti-tumor ability. However, little is known about these alterations in CML patients.MethodHere, we investigated the immunologic phenotypes (CD38/CD69/HLA-DR/CD28/CD57/BTLA/TIGIT/PD-1) of T subsets (TN, TCM, TEM, and TEMRA) in peripheral blood (PB) and bone marrow (BM) from de novo CML patients (DN-CML), patients who achieved a molecular response (MR) and those who failed to achieve an MR (TKI-F) after tyrosine kinase inhibitor (TKI) treatment using multicolor flow cytometry.ResultsCD38 or HLA-DR positive PB CD8+TN and TCM cells decreased in the DN-CML patients and this was further decreased in TKI-F patients. Meanwhile, the level of PD-1 elevated in CD8+ TEM and TEMRA cells from PB in all groups. Among BM sample, the level of HLA-DR+CD8+TCM cells significantly decreased in all groups and CD8+TEMRA cells from TKI-F patients exhibited increased level of TIGIT and CD8+ tissue-residual T cells (TRM) from DN-CML patients expressed a higher level of PD-1 and TIGIT. Lastly, we found a significantly decreased proportion of CD86+ dendritic cells (DCs) and an imbalanced CD80/CD86 in the PB and BM of DN-CML patients, which may impair the activation of T cells.ConclusionIn summary, early differentiated TN and TCM cells from CML patients may remain in an inadequate activation state, particularly for TKI-F patients. And effector T cells (TEM, TEMRA and TRM) may be dysfunctional due to the expression of PD-1 and TIGIT in CML patients. Meanwhile, DCs cells exhibited the impairment of costimulatory molecule expression in DN-CML patients. Those factors may jointly contribute to the immune escape in CML patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the immune pattern of T cell subsets in chronic myeloid leukemia before and after TKI treatment

Yao

Lai

et al. 2023

Front. Immunol.

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“…and T-cell immunoglobulin and mucin-domain containing protein-3 (TIM-3), are overexpressed on T-cells of CML patients at diagnosis [7][8][9] . Interestingly, lymphocyteactivation gene-3 (LAG-3) was expressed on fewer T-cells in CML patients compared with healthy individuals 7 .…”

Section: Introductionmentioning

confidence: 99%

Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia

et al. 2023

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Dysregulation of immune checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), but their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed PD-1, TIM-3, CTLA-4, LAG-3 and TIGIT expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 who sustained treatment-free remission (TFR), 22 who experienced molecular relapse (MolR)). We confirmed our previous finding that absolute numbers of T-regs are increased in MolR patients compared to TFR. The immune checkpoint receptors PD-1, CTLA-4, LAG-3 and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T-cells (CD3+), and T-cell subsets including, CD4+T-cells, CD8+T-cells, and T-regs, in patients who relapsed in comparison to those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available datasets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in CML patients stopping TKI, whilst concomitantly targeting leukemic stem cells, and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in CML patients.

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“…However, activated CD8 + CTLs in myeloid leukemias are dysfunctional and fail to eliminate LSCs in vivo (23, 24, 58-60). In CML, T cell exhaustion at diagnosis has been associated with an increased expression of immune inhibitory receptors and a reduced capacity to produce Th1-cytokines compared to patients in remission (59)(60)(61)(62)(63). Similar to CML, gene expression profiling of CD8 + CTLs from AML patients at diagnosis indicate that CTLs in intermediate and high risk AML are less functional than in favorable risk AML and exhibit an exhaustion immune signature (24).…”

Section: The Adaptive Immune System In Leukemiamentioning

confidence: 99%

“…In CML, numbers and frequencies of effector Tregs in peripheral blood and BM are also increased in CML patients at diagnosis and in patients refractory to tyrosine kinase inhibitor (TKI) treatment (59)(60)(61). These effector Tregs are characterized by the expression of the immune checkpoints PD-1, TIM-3 and CTLA-4, all markers for an increased suppressive activity (61). Anatomically, Tregs in CML are widely distributed throughout the BM parenchyma in mice and humans.…”

Section: Tregs In CMLmentioning

confidence: 99%

Regulation of hematopoietic and leukemia stem cells by regulatory T cells

Riether

2022

Front. Immunol.

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Adult bone marrow (BM) hematopoietic stem cells (HSCs) are maintained in a quiescent state and sustain the continuous production of all types of blood cells. HSCs reside in a specialized microenvironment the so-called HSC niche, which equally promotes HSC self-renewal and differentiation to ensure the integrity of the HSC pool throughout life and to replenish hematopoietic cells after acute injury, infection or anemia. The processes of HSC self-renewal and differentiation are tightly controlled and are in great part regulated through cellular interactions with classical (e.g. mesenchymal stromal cells) and non-classical niche cells (e.g. immune cells). In myeloid leukemia, some of these regulatory mechanisms that evolved to maintain HSCs, to protect them from exhaustion and immune destruction and to minimize the risk of malignant transformation are hijacked/disrupted by leukemia stem cells (LSCs), the malignant counterpart of HSCs, to promote disease progression as well as resistance to therapy and immune control. CD4+ regulatory T cells (Tregs) are substantially enriched in the BM compared to other secondary lymphoid organs and are crucially involved in the establishment of an immune privileged niche to maintain HSC quiescence and to protect HSC integrity. In leukemia, Tregs frequencies in the BM even increase. Studies in mice and humans identified the accumulation of Tregs as a major immune-regulatory mechanism. As cure of leukemia implies the elimination of LSCs, the understanding of these immune-regulatory processes may be of particular importance for the development of future treatments of leukemia as targeting major immune escape mechanisms which revolutionized the treatment of solid tumors such as the blockade of the inhibitory checkpoint receptor programmed cell death protein 1 (PD-1) seems less efficacious in the treatment of leukemia. This review will summarize recent findings on the mechanisms by which Tregs regulate stem cells and adaptive immune cells in the BM during homeostasis and in leukemia.

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Chronic myeloid leukaemia patients at diagnosis and resistant to tyrosine kinase inhibitor therapy display exhausted T‐cell phenotype

Abstract: H. (2022). Chronic myeloid leukaemia patients at diagnosis and resistant to tyrosine kinase inhibitor therapy display exhausted T-cell phenotype.

Cited by 7 publications

References 24 publications

Comprehensive analysis of the immune pattern of T cell subsets in chronic myeloid leukemia before and after TKI treatment

Comprehensive analysis of the immune pattern of T cell subsets in chronic myeloid leukemia before and after TKI treatment

Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia

Regulation of hematopoietic and leukemia stem cells by regulatory T cells

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