The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B‐cell lymphoma and enhances T‐cell recruitment

Yuan, Hepei; Nishikori, Momoko; Otsuka, Yuichi; Arima, Hiroshi; Kitawaki, Toshio; Takaori‐Kondo, Akifumi

doi:10.1111/cas.15122

Cited by 14 publications

(10 citation statements)

References 54 publications

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“…Tazemetostat upregulates the expression of CCL17 in B-cell lymphoma and enhances the recruitment of IFN-γ secreting T cells. In human lymphoma databases, the CCL17 expression level is inversely correlated with the EZH2 activation gene signature and is significantly associated with T-cell–rich microenvironment in FL and Germinal Center B-Cell like (GCB) DLBCLs [ 150 ]. In addition, EZH2 inhibition resulted in significant upregulation of MHC class I expression in mouse models in vivo.…”

Section: Epigenetic Therapy and Time Modulationmentioning

confidence: 99%

Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities

Tien

Lin

et al. 2023

J Biomed Sci

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The tumor immune microenvironment represents a sophisticated ecosystem where various immune cell subtypes communicate with cancer cells and stromal cells. The dynamic cellular composition and functional characteristics of the immune landscape along the trajectory of cancer development greatly impact the therapeutic efficacy and clinical outcome in patients receiving systemic antitumor therapy. Mounting evidence has suggested that epigenetic mechanisms are the underpinning of many aspects of antitumor immunity and facilitate immune state transitions during differentiation, activation, inhibition, or dysfunction. Thus, targeting epigenetic modifiers to remodel the immune microenvironment holds great potential as an integral part of anticancer regimens. In this review, we summarize the epigenetic profiles and key epigenetic modifiers in individual immune cell types that define the functional coordinates of tumor permissive and non-permissive immune landscapes. We discuss the immunomodulatory roles of current and prospective epigenetic therapeutic agents, which may open new opportunities in enhancing cancer immunotherapy or overcoming existing therapeutic challenges in the management of cancer.

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Section: Epigenetic Therapy and Time Modulationmentioning

confidence: 99%

Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities

Tien

Lin

et al. 2023

J Biomed Sci

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“…Tazemetostat is an EZH2 inhibitor that prevents H3K27 methylation. By promoting the buildup of excessive DNA damage, tazemetostat sensitizes cells to genotoxic treatments (such as the use of Top2 inhibitors), resulting in their death [ 138 , 139 ].…”

Section: Chromatin Remodeling and Gene Transcriptionmentioning

confidence: 99%

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Matias-Barrios

Dong

2023

Pharmaceuticals

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DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.

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“…Tazemetostat induces the expression of CCL17 in B-cell lymphoma lines and enhances T-cell recruitment [ 34 ], indicating a potential role in anti-tumor immune responses that may need to be explored in the context of immunotherapies. Tazemetostat has been approved for epithelioid sarcoma treatment [ 35 ], refractory follicular lymphoma [ 36 ].…”

Section: Histone Methylationmentioning

confidence: 99%

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Lazo

2022

Cancers

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Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

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The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B‐cell lymphoma and enhances T‐cell recruitment

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 14 publications

References 54 publications

Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities

Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

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