Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

Radpour, Ramin; Stucki, Miriam; Riether, Carsten; Ochsenbein, Adrian F.

doi:10.3389/fonc.2021.663406

Cited by 16 publications

(16 citation statements)

References 40 publications

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“…Recently, it was observed that bone marrow-infiltrating CD8 + T cells from acute myeloid leukemia (AML) patients demonstrated downregulated expression of immune checkpoint (IC) receptors including PD-1 which could contribute to upregulation of immune checkpoint ligands such as PD-L1 due to poor PD-1/PD-L1 interaction ( 117 ). However, treatment with VPA increased the expression of IC receptors.…”

Section: Effects Of Hdac Inhibitors On Immune Checkpoint Proteinsmentioning

confidence: 99%

“…Likewise, genetic ablation of dual-specificity phosphatase 2 (DUSP2) (a newly identified T cell suppressor and key epigenetic immune modulator acting via HDAC complex) in CD8 + T cells upregulated genes involved in IC receptors. Interestingly, both VPA and DUSP 2 knockdown improved the effector functionality of CD8 + T cells; suggesting that downregulation in IC receptors is associated with pathological HDAC expression and resistance to IC inhibitors ( 117 ). Collectively, these studies depict HDAC inhibitors demonstrate the potential to increase immune checkpoint proteins expression and promote sensitivity to ICB as a combination therapy for ICB resistance in cancer patients.…”

Section: Effects Of Hdac Inhibitors On Immune Checkpoint Proteinsmentioning

confidence: 99%

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Regulating Histone Deacetylase Signaling Pathways of Myeloid-Derived Suppressor Cells Enhanced T Cell-Based Immunotherapy

2022

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Immunotherapy has emerged as a promising approach to combat immunosuppressive tumor microenvironment (TME) for improved cancer treatment. FDA approval for the clinical use of programmed death receptor 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors revolutionized T cell-based immunotherapy. Although only a few cancer patients respond to this treatment due to several factors including the accumulation of immunosuppressive cells in the TME. Several immunosuppressive cells within the TME such as regulatory T cells, myeloid cells, and cancer-associated fibroblast inhibit the activation and function of T cells to promote tumor progression. The roles of epigenetic modifiers such as histone deacetylase (HDAC) in cancer have long been investigated but little is known about their impact on immune cells. Recent studies showed inhibiting HDAC expression on myeloid-derived suppressor cells (MDSCs) promoted their differentiation to less suppressive cells and reduced their immunosuppressive effect in the TME. HDAC inhibitors upregulated PD-1 or PD-L1 expression level on tumor or immune cells sensitizing tumor-bearing mice to anti-PD-1/PD-L1 antibodies. Herein we discuss how inhibiting HDAC expression on MDSCs could circumvent drawbacks to immune checkpoint inhibitors and improve cancer immunotherapy. Furthermore, we highlighted current challenges and future perspectives of HDAC inhibitors in regulating MDSCs function for effective cancer immunotherapy.

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Section: Effects Of Hdac Inhibitors On Immune Checkpoint Proteinsmentioning

confidence: 99%

Section: Effects Of Hdac Inhibitors On Immune Checkpoint Proteinsmentioning

confidence: 99%

Regulating Histone Deacetylase Signaling Pathways of Myeloid-Derived Suppressor Cells Enhanced T Cell-Based Immunotherapy

2022

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“…Upregulation of programmed cell death-ligand 1 (PD-L1) on cancer cells inhibits immune attack via binding to its receptor, programmed cell death protein 1 (PD1), expressed on activated T cells (47). High PD-L1 expression levels have been observed on malignant plasma cells making it a promising target for immune checkpoint inhibitors (ICIs) (18,48,49). In addition, enhanced numbers of PD1 positive and T cell immunoglobulin and mucin domaincontaining protein 3 (TIM3) positive T cells were detected in the BM of MM patients suggesting reduced T cell activation (T cell exhaustion) and an immunosuppressive environment (50).…”

Section: Tumor Infiltrating Lymphocytesmentioning

confidence: 99%

Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease

Förster

Radpour

2022

Front. Oncol.

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Multiple myeloma (MM) is the most common malignant monoclonal disease of plasma cells. Aside from classical chemotherapy and glucocorticoids, proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are used in the current treatment scheme of MM. The tumor microenvironment (TME) plays a fundamental role in the development and progression of numerous solid and non-solid cancer entities. In MM, the survival and expansion of malignant plasma cell clones heavily depends on various direct and indirect signaling pathways provided by the surrounding bone marrow (BM) niche. In a number of MM patients, single plasma cell clones lose their BM dependency and are capable to engraft at distant body sites or organs. The resulting condition is defined as an extramedullary myeloma (EMM). EMMs are highly aggressive disease stages linked to a dismal prognosis. Emerging literature demonstrates that the dynamic interactions between the TME and malignant plasma cells affect myeloma dissemination. In this review, we aim to summarize how the cellular and non-cellular BM compartments can promote plasma cells to exit their BM niche and metastasize to distant intra-or extramedullary locations. In addition, we list selected therapy concepts that directly target the TME with the potential to prevent myeloma spread.

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“…By determining these histone modifications, different chromatin states of region can be defined[ 107 ]. Histone modifications can be subjected to tightening or loose packaging under pathological conditions, including, cancer[ 108 , 109 ]. Histones are modified by specific enzymes.…”

Section: Epigenetic Regulation Of Cscs and Cancer Cellsmentioning

confidence: 99%

Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells

Mandhair¹,

Novak²,

Radpour³

2021

WJSC

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Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.

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Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

Cited by 16 publications

References 40 publications

Regulating Histone Deacetylase Signaling Pathways of Myeloid-Derived Suppressor Cells Enhanced T Cell-Based Immunotherapy

Regulating Histone Deacetylase Signaling Pathways of Myeloid-Derived Suppressor Cells Enhanced T Cell-Based Immunotherapy

Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease

Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells

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