Recent Update of HDAC Inhibitors in Lymphoma

Chen, I-Chung; Sethy, Bidyadhar; Liou, Jing‐Ping

doi:10.3389/fcell.2020.576391

Cited by 57 publications

(59 citation statements)

References 132 publications

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“…It has its pan-HDACi activity in common with the above-mentioned HDACi and is active at a nanomolar to low micromolar range. Belinostat displays low toxicity in patients, and side effects are mostly manageable [ 84 , 95 , 133 , 134 , 135 , 136 ]. Belinostat is potent at inhibiting cell proliferation [ 137 ] and has successfully stimulated cell lines and primary CD4 + T-cells, latently infected with HIV-1, to express virus [ 111 ] ( Table 1 ).…”

Section: Manipulation Of Histone Modificationmentioning

confidence: 99%

Latency Reversing Agents: Kick and Kill of HTLV-1?

Schnell

Kohrt

Thoma-Kress

2021

IJMS

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Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.

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Section: Manipulation Of Histone Modificationmentioning

confidence: 99%

Latency Reversing Agents: Kick and Kill of HTLV-1?

Schnell

Kohrt

Thoma-Kress

2021

IJMS

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“…In addition, HDACi directly acts on tumor cells by upregulating MHC class I molecules and indirectly by eliminating myeloid-derived suppressor cells ( 35 ). Notably, HDACis can increase the expression of immune-related molecules in different cancer types ( 36 , 37 ). In our study, treatment with HDACi increased the gene expression of defined IC receptors mainly in AML BM-infiltrating CD8 + T cells and partially in CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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BackgroundImmune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.MethodsTo analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.ResultsWe observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.ConclusionsOur results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

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“…Despite initial success in T-cell lymphoma and multiple myeloma, most clinical trials for several solid cancers, including ovarian, NSCLC, colorectal and prostate, indicated that HDAC inhibitor monotherapy is not an effective treatment [ 153 , 154 , 155 , 156 ]. This could be due to poor pharmacokinetics and high toxicity profiles [ 157 ], or due to distinct genetic or epigenetic alterations present in hematological cancers [ 79 , 158 ]. Thus, future studies in solid tumors should focus on using HDACi in stratified settings, combinatorial approaches, or enhanced drug delivery methods.…”

Section: Effects Of Hdac Inhibitors and Therapeutic Implications For Tumor Heterogeneitymentioning

confidence: 99%

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

Karagiannis

Ράμπιας

2021

Cancers

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Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.

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Recent Update of HDAC Inhibitors in Lymphoma

Cited by 57 publications

References 132 publications

Latency Reversing Agents: Kick and Kill of HTLV-1?

Latency Reversing Agents: Kick and Kill of HTLV-1?

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

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

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