Abstract LB-074: Priming the tumor microenvironment with epigenetic modifiers to overcome resistance to immune checkpoint inhibitors

Knox, Tessa; Sahakian, Eva; Banik, Debarati; Hadley, Melissa; Palmer, Erica; Kim, Jennifer; Noonepalle, Satish; Powers, John J.; Gracia-Hernandez, Maria; Oliveira, Vasco; Cheng, Fengdong; Chen, Jie; Bařinka, Cyril; Pinilla‐Ibarz, Javier; Lee, Norman; Kozikowski, Alan P.; Villagra, Alejandro

doi:10.1158/1538-7445.sabcs18-lb-074

Cited by 2 publications

(3 citation statements)

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“…Histone modification are a class of post-translational modifications that regulate gene expression, including methylation, acetylation, phosphorylation, adenylylation, ubiquitination (96). The process of acetylation in lysine residues is well studied and regulated by the dynamic balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs), which have opposing functions.…”

Section: Histone Modificationsmentioning

confidence: 99%

“…Generally, acetylation promotes gene expression while deacetylation causes suppression of gene expression. HDAC inhibition enhances histone acetylation, leading DNA to bind tighter and gene expression to reduce (96,97). Several studies have illustrated the regulatory effects of different types of HDAC inhibitors on MDSCs expansion and function through distinct signal pathways (98).…”

Section: Histone Modificationsmentioning

confidence: 99%

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Myeloid-derived suppressor cell: A crucial player in autoimmune diseases

et al. 2022

Front. Immunol.

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Myeloid-derived suppressor cells (MDSCs) are identified as a highly heterogeneous group of immature cells derived from bone marrow and play critical immunosuppressive functions in autoimmune diseases. Accumulating evidence indicates that the pathophysiology of autoimmune diseases was closely related to genetic mutations and epigenetic modifications, with the latter more common. Epigenetic modifications, which involve DNA methylation, covalent histone modification, and non-coding RNA-mediated regulation, refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. Recently, numerous reports have shown that epigenetic modifications in MDSCs play important roles in the differentiation and development of MDSCs and their suppressive functions. The molecular mechanisms of differentiation and development of MDSCs and their regulatory roles in the initiation and progression of autoimmune diseases have been extensively studied, but the exact function of MDSCs remains controversial. Therefore, the biological and epigenetic regulation of MDSCs in autoimmune diseases still needs to be further characterized. This review provides a detailed summary of the current research on the regulatory roles of DNA methylation, histone modifications, and non-coding RNAs in the development and immunosuppressive activity of MDSCs, and further summarizes the distinct role of MDSCs in the pathogenesis of autoimmune diseases, in order to provide help for the diagnosis and treatment of diseases from the perspective of epigenetic regulation of MDSCs.

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Section: Histone Modificationsmentioning

confidence: 99%

Section: Histone Modificationsmentioning

confidence: 99%

Myeloid-derived suppressor cell: A crucial player in autoimmune diseases

et al. 2022

Front. Immunol.

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“…Depending on their cellular localisation, they influence the condensation state of histones, [2] participate in the post‐translational modifications of cytosolic proteins [3] or even might act as an epigenetic reader in the case of class IIa HDACs [4] . Amongst humans, their diverse array of functions renders them a valuable target for the pharmacological intervention of immunological [5–8] or neurodegenerative diseases [9,10] and are clinically validated targets for the treatment of cancer [11] …”

Section: Introductionmentioning

confidence: 99%

Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

et al. 2021

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The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan‐histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk‐benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6‐selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea‐based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea‐based hydroxamic acids. Herein, we report highly potent N‐alkoxyurea‐based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti‐proliferative properties compared to nexturastat A.

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Abstract LB-074: Priming the tumor microenvironment with epigenetic modifiers to overcome resistance to immune checkpoint inhibitors

Cited by 2 publications

References 0 publications

Myeloid-derived suppressor cell: A crucial player in autoimmune diseases

Myeloid-derived suppressor cell: A crucial player in autoimmune diseases

Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

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