Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors

Bae, Jooeun; Hideshima, Teru; Tai, Yu‐Tzu; Song, Yan; Richardson, Paul G.; Raje, Noopur; Munshi, Nikhil C.; Anderson, Kenneth C.

doi:10.1038/s41375-018-0062-8

Cited by 100 publications

(82 citation statements)

References 58 publications

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“…In hematopoietic systems, HDACis have shown synergistic or additive effects with numerous chemotherapeutic agents, such as proteasome inhibitors, hormonal therapy, tyrosine kinase inhibitors, DNAhypomethylating agents, and immune checkpoint inhibitors, in preclinical and clinical settings. HDACis recently emerged as promising immunomodulatory drugs, like TMP195 and ACY241, via modulation of immune cell phenotypes or expression of immune checkpoints [80,172]. Immune checkpoint inhibitors have revolutionized the treatment of hematological malignancies.…”

Section: Resultsmentioning

confidence: 99%

“…The HDAC6 inhibitor ACY1215 or HDAC6 specific silencing resulted in the downregulation of PD-L1 in primary B cells isolated from CLL patients and restoration of CD4:CD8 ratio [79]. Similarly, the HDAC6 inhibitor ACY241 significantly reduces the frequency of CD138+ MM cells, CD4 + CD25 + FoxP3+ regulatory T cells, and decreases expression of PD1/PD-L1 on CD8+ T cells in bone marrow cells from myeloma patients [80]. More recently, the combination of HDAC6 inhibitor and anti-PD-L1 antibody can trigger cytotoxic T lymphocytes and NK cell-mediated MM cell killing.…”

Section: B Cellmentioning

confidence: 95%

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Role of HDACs in normal and malignant hematopoiesis

2020

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Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

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Section: Resultsmentioning

confidence: 99%

Section: B Cellmentioning

confidence: 95%

Role of HDACs in normal and malignant hematopoiesis

2020

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“…Histone deacetylases (HDAC) are a therapeutic target for a variety of cancers. The inhibition of HDAC6 activates the AKT/mTOR/p65 pathway and up-regulates BCL-6, Eomes, HIF-1, and T-bet, thereby increasing the expression of co-stimulatory molecules (CD28, 41bb, CD40L, OX40, and CD38) and activation of antigen-specific memory T cells [156]. B-type TILs are good prognostic markers for most cancers [157].…”

Section: Combination Therapeutic Strategies To Enhance T Cell Activationmentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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“…The current study showed there was a positive correlation between HDAC6 and PD-L1 expression. HDAC6 inhibition enhanced the response to immunotherapy via PD-1/PD-L1 [25].…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Up-Regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients with Advanced Ovarian High-Grade Serous Carcinoma

Yano

Miyazawa

Ogane³

et al. 2020

Preprint

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Abstract Background: Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. In our previous study on ovarian clear cell carcinoma, histone deacetylase 6 (HDAC6) led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and therapeutic target for ovarian HGSC. Methods: We evaluated the clinical significance of HDAC6 as a predictor of prognosis and chemoresistance in HGSC. Immunohistochemical expressions of HDAC6, programmed cell death ligand-1 (PD-L1), and hypoxia inducible factor-1α (HIF-1α) were analyzed using clinical samples from 88 patients with ovarian HGSC. The clinicopathological characteristics were reviewed. Results: Twenty-three patients had high HDAC6 expression; 10, positive PD-L1 expression; and 33, high HIF-1α expression. HDAC6 up-regulation was correlated with not undergoing interval debulking surgery (p < 0.001), incomplete surgical resection (p = 0.002), and frequent occurrence of stable disease/progressive disease according to the RECIST (p = 0.005) criteria. On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with decreased progression-free survival (p = 0.001) and overall survival (p = 0.008). On multivariate analysis, high HDAC6 expression (hazard ratio = 1.65; 95% confidence interval 1.03–2.66, p = 0.039) and surgery status were independent prognostic factors of progression-free survival. PD-L1 and HIF-1α expressions positively correlated with HDAC6. Conclusion: HDAC6 is a potential therapeutic target since HDAC6 up-regulation might cause poor prognosis in patients with ovarian HGSC.

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Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors

Cited by 100 publications

References 58 publications

Role of HDACs in normal and malignant hematopoiesis

Role of HDACs in normal and malignant hematopoiesis

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

WITHDRAWN: Up-Regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients with Advanced Ovarian High-Grade Serous Carcinoma

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