Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Feng, Zhongxin; Fang, Qin; Kuang, Xingyi; Liu, Xin; Chen, Ying; Ma, Dan; Wang, Jishi

doi:10.21203/rs.3.rs-50231/v1

Cited by 4 publications

(4 citation statements)

References 44 publications

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“…Lower diversity of the TCR repertoire may reflect more recognition of certain specific antigen and less responses to diversified antigens. Such restricted recognition implied T cell clones targeting these antigens undergo expansion, which is also called clonal expansion (29). Subsequently, we assessed the gene usage in these two distinct groups.…”

Section: Restricted Tcr Clonotypes Were Revealed In Pgd Compared With Ngd Patientsmentioning

confidence: 99%

Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

Chen¹,

Liu²,

Zhang³

et al. 2021

Front. Endocrinol.

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Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies for pGD, we investigated the role of T cells in the long-lasting phase of GD. Clinical characteristics were compared between the pGD and newly diagnosed GD (nGD) (N = 20 respectively). Flow cytometric analysis was utilized to determine the proportions of Treg and Th17 cells (pGD, N = 12; nGD, N = 14). T cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq) were also performed (pGD, N = 13; nGD, N = 20). Flow cytometric analysis identified lower proportions of Th17 and Treg cells in pGD than in nGD (P = 0.0306 and P = 0.0223). TCR-seq analysis revealed a lower diversity (P = 0.0025) in pGD. Specifically, marked clonal expansion, represented by an increased percentage of top V-J recombination, was observed in pGD patients. Interestingly, pGD patients showed more public T cell clonotypes than nGD patients (2,741 versus 966). Meanwhile, RNA-seq analysis revealed upregulation of the inflammation and chemotaxis pathways in pGD. Specifically, the expression of pro-inflammatory and chemotactic genes (IL1B, IL13, IL8, and CCL4) was increased in pGD, whereas Th17 and Treg cells associated genes (RORC, CARD9, STAT5A, and SATB1) decreased in pGD. Additionally, TCR diversity was negatively correlated with the expression of pro-inflammatory or chemotactic genes (FASLG, IL18R1, CCL24, and CCL14). These results indicated that Treg dysregulation and the expansion of pathogenic T cell clones might be involved in the long-lasting phase of GD via upregulating chemotaxis or inflammation response. To improve the treatment of pGD patients, ATDs combined therapies, especially those aimed at improving Treg cell frequencies or targeting specific expanded pathogenic TCR clones, are worth exploring in the future.

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Section: Restricted Tcr Clonotypes Were Revealed In Pgd Compared With Ngd Patientsmentioning

confidence: 99%

Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

Chen¹,

Liu²,

Zhang³

et al. 2021

Front. Endocrinol.

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“…As a consequence, AML patients—and especially patients with refractory disease or relapse after HSCT—display higher frequencies of exhausted T cells compared to healthy donors [ 12 – 19 ]. The malfunctioning T cell space in AML is also characterized by a general down-regulation of genes involved in T cell activation [ 20 ], as well as a skewed T cell repertoire with reduced diversity compared to healthy donors [ 19 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients

et al. 2022

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Hypomethylating agents (HMA) like azacitidine are licensed for the treatment of acute myeloid leukemia (AML) patients ineligible for allogeneic hematopoietic stem cell transplantation. Biomarker-driven identification of HMA-responsive patients may facilitate the choice of treatment, especially in the challenging subgroup above 60 years of age. Since HMA possesses immunomodulatory functions that constitute part of their anti-tumor effect, we set out to analyze the bone marrow (BM) immune environment by next-generation sequencing of T cell receptor beta (TRB) repertoires in 51 AML patients treated within the RAS-AZIC trial. Patients with elevated pretreatment T cell diversity (11 out of 41 patients) and those with a boost of TRB richness on day 15 after azacitidine treatment (12 out of 46 patients) had longer event-free and overall survival. Both pretreatment and dynamic BM T cell metrics proved to be better predictors of outcome than other established risk factors. The favorable broadening of the BM T cell space appeared to be driven by antigen since these patients showed significant skewing of TRBV gene usage. Our data suggest that one course of AZA can cause reconstitution to a more physiological T cell BM niche and that the T cell space plays an underestimated prognostic role in AML.Trial registration: DRKS identifier: DRKS00004519

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“…As we have previously discussed, thymus involution has been known to result in limited TCR diversity. Several groups have similarly reported restricted TCR repertoire diversity and skewed oligoclonal ab + and gd + T-cell pools in AML (74)(75)(76)(77). Notably, recent studies have shown restricted expression and oligoclonal expansion of certain Vb subfamily T cells, such as PD-1 + Vb T cells in patients with AML and CML (76,77).…”

Section: Thymus' Role In Clonotype Tcr Diversitymentioning

confidence: 98%

The potential role of the thymus in immunotherapies for acute myeloid leukemia

Hino

Xiao

et al. 2023

Front. Immunol.

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Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease’s progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

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Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Cited by 4 publications

References 44 publications

Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients

The potential role of the thymus in immunotherapies for acute myeloid leukemia

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