Reduced regulatory T cells (Treg) in bone marrow preferentially associate with the expansion of cytotoxic T lymphocytes in low risk <scp>MDS</scp> patients

Giovazzino, Angela; Leone, Stefania; Rubino, Valentina; Palatucci, Anna Teresa; G, Cerciello; Alfinito, Fiorella; Pane, Fabrizio; Ruggiero, Giuseppina; Terrazzano, Giuseppe

doi:10.1111/bjh.15496

Cited by 18 publications

(33 citation statements)

References 17 publications

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“…Tregs are high producers of IL10 in the BM and these cells directly regulate MSC function which, in turn, maintain HSCs [145]. One of the emerging pieces of evidence for immune dysregulation in MDS implicates Tregs, which are significantly altered in MDS patients [146][147][148][149], with a decrease in low-risk MDS and an increase in high-risk MDS (Figure 2). The role of Tregs in MDS pathogenesis may potentially explain its strong association with autoimmune disorders and disease progression, considering that dysfunctional and reduced numbers of Tregs can lead to the weakened suppression of excessive immune response, while a high number, along with increased function, can cause the disruption of the immune surveillance machinery against the dysplastic clone(s), therefore allowing for the unhindered proliferation of myeloid blasts.…”

Section: Immune-bmmementioning

confidence: 99%

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Mian

Bonnet

2021

Cancers

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Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.

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Section: Immune-bmmementioning

confidence: 99%

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Mian

Bonnet

2021

Cancers

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“…Several studies have implicated T-cell dysfunction with MDS, consistent with the finding that several MDS patients respond to immunosuppressive treatments (3)(4)(5). For instance, T-cell dysregulation (6,7), T-cell inhibition of hematopoietic precursors (8), and auto-immune T-cell activity may lead to selection of dysplastic clones in MDS (6). Moreover, 10% of MDS patients have autoimmune clinical manifestations including vasculitis, dermatitis and nephritis (9).…”

Section: Introductionmentioning

confidence: 57%

Response to Hypomethylating Agents in Myelodysplastic Syndrome Is Associated With Emergence of Novel TCR Clonotypes

et al. 2021

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Aberrant T-cell function is implicated in the pathogenesis of myelodysplastic syndrome (MDS). Monitoring the T-cell receptor (TCR) repertoire can provide insights into T-cell adaptive immunity. Previous studies found skewed TCR repertoires in MDS compared to healthy patients; however these studies that leverage mRNA-based spectratyping have limitations. Furthermore, evaluating the TCR repertoire in context of hypomethylating agents (HMAs) treatment can provide insights into the dynamics of T-cell mediated responses in MDS. We conducted immunosequencing of the CDR3 regions of TCRβ chains in bone marrows of 11 MDS patients prior to treatment (n=11 bone marrows prior to treatment), and in at least 2 timepoints for each patient following treatment (n=26 bone marrow aspirates post-treatment) with (HMA), alongside analyzing bone marrows from 4 healthy donors as controls. TCR repertoires in MDS patients were more clonal and less diverse than healthy donors. However, unlike previous reports, we did not observe significant skewness in CDR3 length or spectratyping. The global metrics of TCR profiling including richness, clonality, overlaps were not significantly changed in responders or non-responders following treatment with HMAs. However, we found an emergence of novel clonotypes in MDS patients who responded to treatment, while non-responders had a higher frequency of contracted clonotypes following treatment. By applying GLIPH2 for antigen prediction, we found rare TCR specificity clusters shared by TCR clonotypes from different patients at pre- or following treatment. Our data show clear differences in TCR repertoires of MDS compared with healthy patients and that novel TCR clonotype emergence in response to HMA therapy was correlated with response. This suggests that response to HMA therapy may be partially driven by T-cell mediated immunity and that the immune-based therapies, which target the adaptive immune system, may play a significant role in select patients with MDS.

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Section: Abnormal Immune Cell Repartition And/or Functions During The...mentioning

confidence: 99%

“…Clonal CD8 + T-cell expansion is observed in the BM of low-risk MDS patients [ 105 ]. This expansion is associated with a skewed TCR repertoire, suggesting a clonal expansion of tumor-specific CD8 + T cells [ 105 , 106 ]. The identification of tumor antigens represents a promising approach for the development of immunotherapies in MDS, such as tumor antigen vaccination or tumor-specific T-cell adoptive transfer.…”

Section: Abnormal Immune Cell Repartition And/or Functions During The...mentioning

confidence: 99%

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

Simoni

Chapuis

2022

Diagnostics

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Myelodysplastic syndromes (MDS) constitute a very heterogeneous group of diseases with a high prevalence in elderly patients and a propensity for progression to acute myeloid leukemia. The complexity of these hematopoietic malignancies is revealed by the multiple recurrent somatic mutations involved in MDS pathogenesis and the paradoxical common phenotype observed in these patients characterized by ineffective hematopoiesis and cytopenia. In the context of population aging, the incidence of MDS will strongly increase in the future. Thus, precise diagnosis and evaluation of the progression risk of these diseases are imperative to adapt the treatment. Dysregulations of both innate and adaptive immune systems are frequently detected in MDS patients, and their critical role in MDS pathogenesis is now commonly accepted. However, different immune dysregulations and/or dysfunctions can be dynamically observed during the course of the disease. Monitoring the immune system therefore represents a new attractive tool for a more precise characterization of MDS at diagnosis and for identifying patients who may benefit from immunotherapy. We review here the current knowledge of the critical role of immune dysfunctions in both MDS and MDS precursor conditions and discuss the opportunities offered by the detection of these dysregulations for patient stratification.

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Reduced regulatory T cells (Treg) in bone marrow preferentially associate with the expansion of cytotoxic T lymphocytes in low risk MDS patients

Cited by 18 publications

References 17 publications

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Response to Hypomethylating Agents in Myelodysplastic Syndrome Is Associated With Emergence of Novel TCR Clonotypes

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

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