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Publications > Journals > Cancer Screening and Prevention > Article Full Text

  • Review Article
  • OPEN ACCESS

The Heightened Importance of EZH2 in Cancer Immunotherapy

  • Xiao-Hu Lin1,2,3,
  • Wen-Kai Zhou1,2,3,
  • Cheng-Zhong Lin2,3,4,*  and
  • Wei Cao1,2,3,5,* 
 Author information
Cancer Screening and Prevention   2023;2(2):117-129

doi: 10.14218/CSP.2023.00006

Abstract

The transcriptional inhibitor histone methyltransferase enhancer of zeste homolog 2 (EZH2) predominantly targets genes involved in tumor suppression. EZH2 is highly expressed in a variety of human malignancies and promotes carcinogenesis and malignant transformation. Recent research has indicated that altering the tumor microenvironment by focusing on epigenetic variables can improve antitumor immunity. Recent research has also revealed that EZH2 has pleiotropic functions in immune and malignant cells. EZH2 inhibition could be a promising strategy to improve the outcomes of current immunotherapies. Based on the role of EZH2 in the immunomodulation of both immune and tumor cells, we evaluated the effect of EZH2 on tumor immunity in this review. We also highlight improvements in combined EZH2-targeted treatment and immunotherapy.

Keywords

EZH2, Tumor immunity, Immune checkpoint, Metabolism, Immunotherapy

Introduction

Enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of histone methyltransferase and Polycomb-repressive complex 2 (PRC2). EZH2 catalyzes the monomethylation, demethylation, and trimethylation of lysine 27 in histone H3 (H3K27me3). Histone labeling is related to tight chromatin and transcriptional inhibition.1 The EZH2 gene is highly expressed in a wide range of cancers, including head and neck cancer,2–4 breast cancer,5 prostate cancer,6 bladder cancer,7 colorectal cancer,8 lung cancer,9,10 pancreatic cancer,11 melanoma,12 and lymphoma.13 In addition, somatic EZH2 gene mutations were found in 22% of primary B-lymphomas, 7% of follicular lymphomas, and 12–23% of patients with myelodysplastic and myeloproliferative diseases.13–18 Consequently, the function of EZH2 in tumors should be established based on the type of tumor. EZH2 can function as both a tumor suppressor in a small number of T-cell leukemias and myelodysplastic syndromes as well as an oncogene in the majority of solid tumors and lymphomas. Because EZH2 plays a significant role in cancer, EZH2-targeted therapy has emerged as a crucial therapeutic approach in a number of cancers.19 Currently, a number of EZH2 inhibitors (EZH2i) have been created, including tazemetostat, which has received FDA approval for the treatment of follicular lymphoma and epithelioid sarcoma.

There is convincing evidence that EZH2 affects both immune and tumor cells in a pleiotropic manner. As a result, EZH2-targeted medications can control the antitumor immune response.20–23 Presently, immunotherapy is regarded as the fourth pillar of cancer treatment, following radiation, chemotherapy, and surgery.24 Malignant cells can, however, occasionally evade immune surveillance through a number of mechanisms,25–28 proliferate quickly in the body, and potentially lead to tumors. Immunotherapies to suppress immune escape, such as immune checkpoint inhibitor therapy, chimeric antigen receptor T-cell (CAR-T) immunotherapy, and immune cell therapy, have seen significant success in recent years with the investigation of immune escape pathways.29–31 Nevertheless, some cancers continue to show treatment resistance; as a result, using immunotherapy in conjunction with EZH2i could be an excellent way to block tumor immunosuppression. There is evidence that EZH2 inhibition may help improve prognosis for some cancer patients and enhance the effectiveness of already-in-use immunotherapies.32–34

To maximize the potential of epigenetic medicines, a deeper knowledge of EZH2 in cancer immunity is needed. Here, we discuss the function of EZH2 in tumor immune regulation, including its impact on both immune and tumor cells, and the status of EZH2i in combination with anticancer immunotherapies.

Structure and action mode of EZH2

The EZH2 gene is located on chromosome 7q35 and contains five functional domains: a C-terminal SET domain, an adjacent cysteine-rich CXC domain, domain I, domain II and an EED interaction domain (EID) (Fig. 1).1,35 The histone methyltransferase active site is located in the SET domain, and the CXC domain also participates in this activity.36,37

Characterized domains of EZH2.
Fig. 1  Characterized domains of EZH2.

Five functional domains: a C-terminal SET domain, an adjacent cysteine-rich CXC domain, domain I, domain II and an EED interaction domain (EID).

EZH2 exhibits the following modes of action: (1) Chromatin compaction is encouraged by PRC2-dependent histone methylation: H3K27 trimethylation mediated by EZH2 induces transcriptional silence of downstream genes. For instance, it has been demonstrated that the silencing of foxc1 and E-cadherin by EZH2 promotes cancer development.38,39 (2) PRC2-dependent non-histone protein methylation: New evidence suggests that in addition to histones, EZH2 also methylates non-histone proteins, such as signal transducer and activator of transcription 3 (STAT3),40 GATA binding protein 4,41 and RAR-related orphan receptor α,42 leading to their activation and thereby enhancing tumorigenicity. (3) PRC2-independent gene transactivation: EZH2 can also act as a co-activator of PRC2-independent transcription factors. For instance, EZH2 interacts physically with RelA and RelB in breast cancer to enhance NF-κB target expression and tumorigenesis.43 Furthermore, it has been demonstrated that when EZH2 is phosphorylated at Ser21 it behaves as a transcriptional coactivator of the androgen receptor (AR) (Fig. 2).44

Action mode of EZH2 and its effect on tumor cells.
Fig. 2  Action mode of EZH2 and its effect on tumor cells.

As part of PRC2, EZH2 methylates histone 3 at lysine 27 (H3K27), which contributes to transcriptional silencing, thus promoting glycolysis and reducing the expression of MHC in the tumor. EZH2 is also capable of methylating a number of non-histone protein substrates, such as STAT3, which promotes PD-L1 expression in tumor cells. In addition, EZH2 has a PRC2-independent role in transcriptional activation.

Genes directly regulated by EZH2, especially the expression of immune escape and other related genes, are presented in Table 1.45–61

Table 1

Important genes directly regulated by EZH2

Gene NameFunction
BCL650EZH2 can suppress the expression of BCL6 by mediating H3K27me3 modification, thereby reducing the immune recognition and antigen presentation ability of tumor cells.
CD8A51,52EZH2 can inhibit the expression of CD8A by regulating H3K27me3 modification, thereby reducing the immune recognition and clearance effect of tumor cells.
CDKN2A53,54Tumor suppressor gene that inhibits cell proliferation and induces apoptosis, silenced or inactivated in many types of tumors.
CTLA447EZH2 can suppress CTLA4 expression by mediating H3K27me3 modification, thereby weakening T cell immune activity.
E-cadherin55Cell adhesion molecule that promotes cell-cell adhesion and tissue structure stability.
FOXP356EZH2 can suppress FOXP3 expression by mediating H3K27me3 modification, thus reducing the number and function of regulatory T cells (Treg).
IDO145EZH2 can suppress IDO1 expression by mediating H3K27me3 modification, thereby reducing T cell activity in the tumor microenvironment.
NKG2D48EZH2 can suppress NKG2D expression by mediating H3K27me3 modification, thereby reducing the sensitivity of tumor cells to NK cell attack.
PD-146EZH2 can suppress PD-1 expression by mediating H3K27me3 modification, thereby enhancing the immune evasion ability of tumor cells.
PD-L157EZH2 can suppress PD-L1 expression by mediating H3K27me3 modification, thereby reducing the attacking ability of T cells.
RUNX358Transcription factor involved in cell cycle and fate decision-making, acts as a tumor suppressor gene and is silenced or inactivated in many types of tumors.
TIMP259EZH2 can suppress the expression of TIMP2 by mediating H3K27me3 modification, while TIMP2 is a gene that inhibits tumor cell invasion and metastasis.
TIMP360Metalloproteinase inhibitor that inhibits cell migration and invasion, acts as a tumor suppressor gene and is silenced or inactivated in many types of tumors.
TNF49EZH2 can suppress TNF expression by mediating H3K27me3 modification, thereby reducing the immune reaction caused when tumor cells are attacked by T cells.
VEGFA61Vascular endothelial growth factor A, promotes tumor angiogenesis and cell migration, acts as an oncogene and is overexpressed in many types of tumors.

EZH2-mediated immunomodulation in tumor cells

Immune checkpoints

Recent research has revealed a strong connection between EZH2 and the expression of tumor immune checkpoints. Immunohistochemical evaluation of resected lung adenocarcinoma tissue revealed a significant connection between EZH2 and programmed death ligand 1 (PD-L1) expression.62 Studies have further demonstrated that the interaction between the chromatin remodeling SWI/SNF complex and the PRC2 complex regulates the expression of PD-L1.45 By increasing the levels of H3K27me3 in the CD274 and interferon regulatory factor (IRF) 1 promoters without influencing the activation of the IFN-signaling pathway or the STAT1 transcription activator, EZH2 can reduce the expression of PD-L1.63 Production of the T helper cell 1 (Th1) chemokines CXCL9/10 and the subsequent infiltration of effector T cells into tumors can be inhibited by EZH2-mediated DNA methylation linked to DNA methyltransferase DNMT1 and H3K27me3, which improves the clinical effectiveness of PD-L1 immune checkpoint blocking (ICB).64 EZH2 inhibition can upregulate genes involved in antigen presentation, Th1 chemokine signaling, and the interferon response by activating the dsRNA-STING-ISG stress response, including STING activation-dependent PD-L1 expression. This evidence is presented in studies that show EZH2 has a negative regulatory effect on interferon-stimulated genes (ISGs).46 Additionally, EZH2 controls the expression of PD-L1 in non-small cell lung cancer (NSCLC) 65 through increasing HIF-1.65

New immunological checkpoints are also important to study. A number of immunological cells express lymphocyte activating gene-3 (LAG-3), which can decrease CD8+ T cell activity and boost T regulatory cell (Treg) immunosuppressive activity. Treatment of patients with metastatic or incurable melanoma using LAG-3 targeting therapy in conjunction with anti-PD-1 therapy has been demonstrated to be beneficial in clinical trials. Numerous immune cells and other cells express the T cell immunoglobulin and mucin domain-3 (TIM-3). By promoting CD8+ T cell death, TIM-3 interacts with four ligands to inhibit antitumor immunity. Studies have demonstrated that the costimulatory molecules TIM-3/galectin9 are significantly regulated by EZH2-mediated epigenetic regulation in cervical cancer.66 Additionally, research has demonstrated that the EZH2 inhibitors DZNep and GAK126 can suppress LAG-3 and TIM-3 by facilitating the movement of effector T cells.67

Major histocompatibility complex (MHC)

According to the literature, EZH2 suppresses MHC-I and MHC-II, and inhibiting EZH2 can improve the response to immune checkpoint blockade and restore the immunogenicity of some malignancies (ICB).68 A transactivator protein called CIITA can control MHC-II molecule transcription to improve the immunological response. It has been noted that in various tumor types, EZH2 suppresses CIITA through methylation.69 The prosurvival EZH2 Y641 mutation in diffuse large B-cell lymphoma is also the genetic mechanism underpinning MHC-II deficiency, which results in immune surveillance evasion and poor prognosis.70 Increased MHC-I expression has been observed in vitro in lung cancer cells with EZH2 gene deletion or pharmacological suppression of EZH2, which facilitates CD8+ T cell-mediated tumor cell killing.71 Similar to prostate cancer, head and neck squamous cell carcinoma is characterized by overexpression of the MHC-I gene in response to EZH2 inhibition.72,73

Metabolic reprogramming and immune escape

It is generally recognized that tumor occurrence and development are primarily influenced by metabolic disorders. Recent research has suggested that EZH2 may be crucial in controlling cell metabolism. Therefore, by interfering with cellular metabolic processes, EZH2 can impact the growth and spread of malignancies. Studies have shown that tumors, even in the presence of enough tumor antigens for T-cell recognition, can suppress the activity of tumor-infiltrating T cells by competitive glucose uptake. Additionally, tumor cell glycolysis may restrict the amount of glucose that TILs may consume, leading to T-cell failure and immunological escape.

Glucose metabolism

High EZH2 expression in hepatocellular carcinoma was positively connected with Myc expression and the glycolytic signaling pathway and negatively correlated with interferon signaling, according to gene enrichment analysis.74 By elevating the expression of H3K27me3 in the EAF2 promoter region, EZH2 can induce a transition from mitochondrial respiration to glycolysis in glioblastoma cells in vitro. As a result, the transcription of downstream metabolism-related genes such as hexokinase 2 (HK2), glucose transporter 1 (GLUT1), and pyruvate dehydrogenase kinase 1 is induced.75 This inhibits the transcription of EAF2 and activates the HIF-1 signaling pathway. In NSCLC, a similar outcome has been observed. LINC00301 is substantially expressed and is directly correlated with prognosis. By controlling the EZH2/EAF2/HIF-1 axis, LINC00301 recruits EZH2 and mediates H3K27me3 in the EAF2 promoter to restrict EAF2 transcription, boosting the population of Tregs in tumors and decreasing CD8+ T cell infiltration.76 Furthermore, in patients with oral squamous cell carcinoma (OSCC), overexpression of EZH2 promotes cell invasion and migration, as well as glycolysis-mediated epithelial-mesenchymal transition. Additional research revealed that ectopic overexpression of EZH2 promotes tumor development and glycolysis in OSCC by suppressing FoxO1 expression and increasing STAT3 phosphorylation at residue 705.77 Furthermore, through suppressing the expression of particular miRNAs, EZH2 might indirectly activate aerobic glycolysis in cancer cells. HK2, GLUT1, and ribosomal protein S6 kinase B1 are three important glycolytic enzyme-encoding genes that exhibit favorable correlations with EZH2 expression in prostate cancer. HK2 is the downstream target of MiR-181b. By raising its H3K27me3 level, EZH2 indirectly upregulates the expression of HK2 by suppressing the activity of miR-181b.78 When the EZH2 level is low, the glycolytic capacity and reserve in glioma cells are decreased. By attaching to the miR-328 promoter and aiding in its methylation, EZH2 inhibits miR-328 production. Additionally, it was discovered that blocking miR-328 inhibited β-catenin expression. An increase in the extracellular acidification rate, which corresponds to an increase in glycolytic capability, is caused by this EZH2/miRNA/β-catenin feed-forward loop.79

Although competitive uptake of glucose in the tumor microenvironment (TME) is the reason for impaired T-cell function, the levels of amino acids, glutamine, fatty acids, and other metabolites or growth factors and the expression of the corresponding transporters on the cell surface are also important factors affecting the function of immune cells.

Fatty acid metabolism

Evidence suggests that EZH2 greatly favors the synthesis of fat.80,81 Studies have demonstrated that elevated tumor adipogenesis speeds up tumor growth in mice and impairs CD8+ T cell activity in the TME.82 In gliomas with mutations in the telomerase reverse transcriptase (TERT) promoter, there is increased expression of EZH2. Peroxisome proliferator-activated receptor-coactivator-1, which is involved in the production of fatty acid synthase, is activated by TERT and EZH2 together. Both lipid metabolism and TERT expression are impacted by EZH2 knockout. Therefore, it is clear that EZH2 activates the TERT-EZH2 axis, which stimulates fatty acid production and lipid accumulation.83 However, some research has indicated that EZH2 inhibition can cause fat accumulating in breast cancer and liver cell lines.84,85 This disparity can be brought on by variations in the species or adipocyte progenitor lineage. Therefore, further research is needed to determine the possible mechanism through which EZH2 influences lipid metabolism.

Amino acid metabolism

Glutamine uptake plays an important role in many metabolic processes in T lymphocytes, including the tricarboxylic acid cycle (TCA), nucleotide synthesis, and detoxification of reactive oxygen species.86 Studies have revealed that glutamine metabolism increases and suppresses T lymphocyte metabolism in tumors with EZH2 inactivating mutations, increasing tumor progression.87,88 An isoenzyme known as BCAT1 catalyzes the reversible transfer of amino groups on branched chain amino acids. EZH2 inhibits BCAT1 by modifying H3K27me3 during normal hematopoiesis. By activating BCAT1, EZH2 inactivation and the carcinogenic activity of NRAS promote branched chain amino acid metabolism and mTOR signal transduction, and together they facilitate the conversion of myeloproliferative neoplasms into leukemia.89 Accordingly, EZH2-inactivated leukemia stem cells showed active glutamine consumption and elevated expression of TCA cycle genes after EZH2 deletion.87 Additionally, through promoting SAM production, EZH2 may control the metabolism of amino acids. Methionine is a precursor to SAM, which is necessary for tumor cells to methylate DNA and histones.90 Methionine is a necessary amino acid that can be transported by the amino acid transporter Lat1.91 Retinoid X receptor (RXR) derepression is caused by small molecule inhibition or knockdown of EZH2, which decreases Lat1 expression.92 As a result, the EZH2/Lat1 positive feedback loop can promote the production of SAM, which will increase the histone methyltransferase activity of EZH2 and expedite tumor growth.

Impact of EZH2 on immune cells

It is understood that the pathogenic mechanism of cancer involves host immunological dyshomeostasis in solid tumors. Recent research demonstrated that EZH2 controls how different immune cells differentiate and function.93 To shed light on the immunotherapeutic implications of EZH2 in immune cells, we have outlined the main functions of EZH2 in immune cells, which can be divided into two groups: immune cells derived from common lymphoid progenitor cells and immune cells derived from common myeloid progenitor cells.

Impact of EZH2 on immune cells derived from common lymphoid progenitor cells

Hematopoietic stem cell (HSC)

EZH2 is thought to support the maintenance of HSCs by inhibiting cell cycle regulators like Cdkn2.94,95 Defects in other parts of PRC2, such as SUZ12 and EED, may also affect HSC function.96,97 EZH2 controls the strict regulation of thymic T lymphocytes. H3K27me3 levels in thymic progenitor cells drop due to EZH2 deficiency, and Cdkn2a expression rises as a result, increasing thymocyte block in the double-negative (DN) phase. As a result, the number of cells can be partially maintained when EZH2 and Cdkn2a are both lost. These findings imply that EZH2-induced methylation inhibits cell cycle inhibitors to control thymocyte development.98,99

CD4+ T cells

CD4+ Th cells typically coordinate the activation of immune responses by differentiating into multiple lineages, such as Th1, Th2, Th17, and T follicular helper cell (Tfh) subsets, which each play a specific function in antitumor immunity. DNA methylation and histone modification are carefully coordinated to control the flexibility of CD4+ T cell differentiation.100,101 Following T cell-specific EZH2 deletion, CD4+ T cells displayed changes in H3K27me3 levels and the expression of distinctive transcription factors such T-bet, STAT2 and GATA-3, which increased cytokine production and aided in the differentiation of CD4+ T cells into effector Th1 and Th2 cells.102,103 Additionally, EZH2-deficient Th1 and Th2 cells secreted more Th1 and Th2 cytokines, such as IFN-γ, IL-4, and IL-13, indicating that EZH2 often inhibits the expression of particular cytokines. EZH2 increases survival rates and maintains the tumor immune response by inhibiting the expression of apoptosis-related target genes, such as FAS, TNFR1, DR4, and Mlkl1 in effector CD4+ T cells.104–107 Recent research has also demonstrated that expression of the major Th17 transcription factor ROR is increased in mouse embryonic fibroblasts following EZH2 deletion, indicating that EZH2-mediated ROR methylation can promote breakdown of ROR and prevent Th17 cell differentiation.42 However, only a very modest increase in IL-17 production and ROR expression was found in EZH2 mutant CD4+ T cells cultivated under Th17 induction conditions.104 This indicates that controlling Th17 differentiation may not be possible only through EZH2’s epigenetic mechanism. The ability of B cells to undergo somatic hypermutation, affinity maturation, and differentiation into plasma cells and memory B cells can all be increased by Tfh cells, a distinct subgroup of CD4+ T cells.108 Tfh cells are essential for triggering a defense against infection and antibody response.109,110 H3K27ac rather than H3K27me3 is connected with the promoter of the distinctive Tfh transcription factor BCL6, which suggests that EZH2 may not be an important player in these processes.111 The fact that T cell factor 1 recruits EZH2 to directly activate BCL6 transcription and that BCL6 requires EZH2 to be phosphorylated at Ser21 for it to work suggests an unexpected purpose for EZH2 in controlling the fate of Tfh cells.112,113 Additionally, EZH2 reduces Cdkn2a expression via controlling H3K27me3, which impacts the proliferation and death of Tfh cells.112 The impact of EZH2 inhibition on Tfh differentiation in various cancer types needs to be further investigated in light of the mounting evidence that the development of ectopic tertiary lymphoid structures containing Tfh cells may be a favorable prognostic sign during immunotherapy.110

Tregs

Tregs maintains immune tolerance and internal environmental stability by inhibiting the inflammatory response and play an important role in inhibiting antitumor immunity.114–117 Tregs are typically CD4+ T cell subsets that express Foxp3, a transcription factor that is crucial for the differentiation and operation of Tregs.118,119 Silencing of genes typically produced by CD4+ T effector (Teff) cells is linked to the H3K27me3 alteration in the Foxp3 binding site, which EZH2 can support.120 EZH2 is essential for Treg activation in addition to controlling Treg differentiation. Studies have demonstrated that the expression of EZH2 is much higher in activated Tregs than in dormant or quiescent Tregs.120 In comparison to normal tissues, there are more Tregs present among tumor-infiltrating tumors,121 and EZH2 expression was simultaneously elevated in these Tregs.122,123 Recent research has demonstrated that, following the activation of the costimulatory receptor CD28, EZH2 is the chromatin modification that is most strongly increased in mouse Treg cells. Its expression aids in suppressing the phenotype of CD4+ Teff cells and stabilizing the functional phenotype of activated Tregs.123 In summary, targeting EZH2 expression in Tregs in tumors may be a potentially efficient way to improve antitumor immunity.119,122,124 To illustrate the positive potential of EZH2 inhibitor and anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) therapy, suppression of EZH2 expression in Tregs can enhance the antitumor response caused by anti CTLA-4 treatment.47

CD8+ T cells

The proliferation of CD8+ T cells, which differentiate into enough CD8+ T effector cells to significantly reduce the number of tumor cells expressing antigens or into long-lived memory CD8+ T (Tm) cells to rapidly react to repeatedly presented antigens, is stimulated by antigens produced by cancer cells.125,126 It has been demonstrated that the amount of EZH2 expression in renal cell carcinoma is correlated with a high density of CD8+ T cells.127,128 Immature CD8+ T cells with EZH2 deficiency exhibit decreased proliferation and elevated apoptosis in response to antigen stimulation.129–131 Additionally, EZH2 controls how immature CD8+ T cells differentiate. After TCR activation, EZH2-deficient CD8+ naive T cells showed impaired memory cell differentiation.132 According to mounting evidence, EZH2 apparently has a significant impact on T-cell exhaustion in addition to its immunological editing effects. When patients with solid tumors experience this condition, the clinical outcomes are typically not favorable.133–135 A versatile zinc finger transcription factor called Yin Yang-1 (YY1) is engaged in numerous cellular and molecular processes. It recruits EZH2 to inhibit the expression of IL-2. The dysregulation of exhausted T cells is characterized by persistent T-cell activation, which upregulates YY1 and EZH2, epigenetically silencing IL-2.135,136

B cells

B lymphocytes are the primary effector cells of humoral immunity.137,138 High T cell and B cell numbers are viewed as indicators of successful therapeutic outcomes.139,140 EZH2 actively alters the epigenome at various B-cell development phases. While remaining at a low expression level in dormant and immature B cells, EZH2 is strongly expressed in proliferating B cells, such as pre-B cells and germinal center (GC) B cells.141–143 ZH2 inhibits germline Ig transcription and takes part in variable (V), diversity (D), and joining (J) recombination in pre-B cells.144 By blocking the cell cycle inhibitors Cdkn1a and Cdkn1b, EZH2 stimulates the growth of GC B cells, but it inhibits their final differentiation into antibody-secreting cells (ASCs).142,143,145,146 EZH2 is therefore required for B cells to respond to immunological activation. According to the literature, the EZH2 inhibitor EPZ-6438 decreases pre-B cell and B cell proliferation, speeds up the transcriptional modifications that mediate the differentiation of B cells into plasma cells associated with the induction of plasma cell maturation, and increases immunoglobulin secretion.147 Additionally, the total limit on B-cell proliferation is abolished by the EZH2 Y641 mutation in follicular lymphoma, leading to malignant proliferation.148 The therapeutic benefit is lessened by the fact that EZH2 suppression in hepatocellular carcinoma cells can encourage B cells to differentiate into IgG+ plasma cells, which have a tumor-promoting effect.149 This finding shows that consideration should be paid to B cell interference and the requirement for a combined B-cell deletion treatment during EZH2 inhibitor therapy.

NK cells

NK cells are natural lymphocytes that actively engage in the body’s immune response. They have powerful cytolytic activity, the ability to recognize and manifest cytotoxicity toward cancer cells, and the ability to resist the growth of tumors and microbial infections.150–153 The phenotypic change, proliferation, activation, and cytotoxic activity of NK cells are all significantly influenced by EZH2. According to the literature, EZH2 deletion or functional inhibition considerably boosts the quantity and caliber of NK cells.131,154 By directly boosting NK-cell killing in hepatocellular cancer, EZH2 inhibition can upregulate MHC I polypeptide-related sequences.48,155 Interestingly EZH2 expression is inherently downregulated by NK cells in prostate cancer cells, demonstrating the anticancer effect of NK cells on EZH2 inhibition rather than on direct tumor cell killing.156 Additionally, EZH2 inhibition induces enhanced expression of NKG2D, CD122, TLRs, and granzymes necessary for tumor cell elimination, which in turn boosts the activity of mature NK cells.157 As a result, the ability of EZH2 inhibitors to control NK-mediated death has gained more and more attention. Oncogenes implicated in antigen processing, antigen presentation, and NK cell-mediated cytotoxicity are activated when EZH2 inhibitors and DNA methyltransferase inhibitors are combined.158

Impact of EZH2 on immune cells derived from common myeloid progenitor cells

Tumor-associated macrophages (TAMs)

The survival and growth of tumor cells can be boosted by TAMs, and they can also foster an immunosuppressive microenvironment that aids in the development of tumors. TAMs can be divided into two groups: M1 type, which has anticancer effects, and M2 type, which has tumor-promoting effects.159 Inflammatory chemokines and cytokines released from tumor cells have an impact on TAM polarization.160 When PTEN is lost on chromosome 10 in gliomas, EZH2 inhibits miR-454-3p and increases N(6)-methyladenosine (m6A) modification of PTEN, which causes TAM polarization toward the M2 type.161 When EZH2 is inhibited in glioblastoma multiforme cells, macrophages cocultured with microglia can repolarize from the M2 phenotype to the M1 phenotype, which enhances the phagocytic ability of microglia.162–166 By releasing cytokines such as IL-8, macrophage inflammatory protein-3, and IL-1, M2 TAMs stimulate the development of glioma cells.161,167,168 In lung cancer, EZH2 mediates H3K27me3 in the CCL2 enhancer region and inhibits the infiltration of M1 TAMs in the TME, thus promoting tumor development, and these effects can be reversed by epigenetic inhibitors.169 Additionally, lung cancer cells that express EZH2 are more likely to produce CCL5, which can attract M2 TAMs and facilitate metastasis and macrophage infiltration.33,170 By targeting hepatocyte growth factor and macrophage migration inhibitory factor, EZH2-mediated suppression of the miR-144/miR-451a cluster boosts antitumor immunity and promotes M1 polarization of TAMs.171 Additionally, it has been demonstrated that miR-17, which is carried by bone marrow stem cell-derived extracellular vesicles, affects the EZH2/trail axis to reduce macrophage inflammatory responses.172 The aforementioned findings demonstrate that the detrimental impact of EZH2 inhibitors on macrophage function should be taken into account.

Dendritic cells (DCs)

In contrast to monocytes, which can only differentiate from common myeloid progenitor cells, DCs can differentiate from both common lymphoid progenitor cells and myeloid progenitor cells. The primary job of DCs is to present antigens. In vivo tests demonstrated that EZH1 compensated for EZH2 loss in mature DCs.173 But according to other research, EZH2 inhibition can lessen the inflammatory response mediated by DCs and minimize liver damage by increasing the expression of the tumor suppressor gene RUNT-related transcription factor 1 in bacteria-induced liver injury.174,175 Additionally, the recruitment of EZH2 by the active form of STAT5B modulates IRF4 and IRF8 expression to generate tolerogenic DC function.176 As a result, little is known about how EZH2 might affect DC activity and how that might affect tumor immunity.173,177 Understanding the impact of EZH2 on DCs is essential given the significance of DCs in anticancer immunity.

The multiple functions of EZH2 in different immune cells are shown in Figure 3.

EZH2 has multiple functions in different immune cells.
Fig. 3  EZH2 has multiple functions in different immune cells.

EZH2 mediates the activation, differentiation, proliferation, and phenotypic transformation of a variety of immune cells, plays a role in tumor promotion and tumor inhibition, and finally regulates cancer cell proliferation, tumor growth, and invasion.

Combinations of EZH2 inhibition and immunotherapy

Surface EZH2 is a crucial regulator of cancer immune editing because of the regulatory effects of EZH2 on immune and tumor cells that have been previously discussed. To enhance the therapeutic efficacy and circumvent the drawbacks of monotherapy, it is worthwhile to weigh the benefits of combining immunotherapies with clinically available EZH2 inhibitors.

According to recent research, EZH2 inhibitor therapy and ICB therapy can overcome medication resistance that develops during treatment. Combination therapy for prostate cancer that includes an immune checkpoint inhibitor and an EZH2 inhibitor can lessen the prostate cancer resistance to PD-1 inhibitors and boost the effectiveness of prostate cancer immunotherapy by inhibiting EZH2.46 The Th1 chemokines CXCL9 and CXCL10 were increased in a mouse model of human ovarian cancer following EZH2 inhibition, increasing the infiltration of effector T cells and enhancing the therapeutic effects of PD-L1 ICB treatment and adoptive T-cell infusion in tumor-bearing mice.178 Additionally, anti-CTLA-4 therapy increased the expression of EZH2 in melanoma cells and decreased immunogenicity and antigen presentation in a mouse melanoma model. Melanoma growth was shown to be greatly slowed by EZH2 suppression and anti-CTLA-4 therapy.49 According to the study, anti-CTLA-4 therapy impacted the function of T cells by increasing EZH2 expression in peripheral T cells. The therapeutic impact can be greatly increased by combining treatment with an EZH2 inhibitor in mouse models.47 Recent research has demonstrated that EZH2 inhibitors increase the immunological checkpoint PD-1 in malignant pleural mesothelioma, and it is thought that using EZH2 inhibitors and PD-1 blockers together can increase macrophage toxicity and hence increase the effectiveness of immunotherapy.179 According to the aforementioned research, the combination of EZH2 inhibitor therapy and ICB therapy will have significant clinical implications, particularly in malignancies that do not respond to or are resistant to ICB medications. Another study found that the combination of EZH2 inhibitor medication with CAR-T therapy can enhance the therapeutic efficacy of CAR-T therapy by boosting the expression of tumor-associated antigens in Ewing sarcoma.180

In conclusion, combinations with various immunotherapies should be further researched to determine the best therapeutic approach and any potential side effects of the EZH2 inhibitor medication in combination with immunotherapy. Further ongoing clinical trials are summarized in Table 2.

Table 2

Ongoing clinical trials of EZH2 inhibitors

Drug(s)Disease(s)Phase
TazemetostatMesothelioma; BAP1 loss of functionII (NCT02860286)
TazemetostatMalignant rhabdoid tumors (MRTs); Rhabdoid tumors of the kidney (RTKs); Atypical teratoid rhabdoid tumors (ATRTs); Selected tumors with rhabdoid features; Synovial sarcoma; INI1-negative tumors; Malignant rhabdoid tumor of ovary; Renal medullary carcinoma; Epithelioid sarcoma; Poorly differentiated chordomaII (NCT02601950)
TazemetostatRhabdoid tumors; INI1-negative tumors; Synovial sarcoma; Malignant rhabdoid tumor of ovaryII (NCT02601937)
TazemetostatB-cell lymphomas (Phase 1); Diffuse large B-cell lymphoma (Phase 2); Follicular lymphoma (Phase 2); Transformed follicular lymphoma; Primary mediastinal large B-cell lymphomaI/II (NCT01897571)
SHR2554Relapsed or refractory mature lymphoid neoplasmsI (NCT03603951)
SHR2554; SHR1701LymphomaI/II (NCT04407741)
Dabrafenib mesylate; Tazemetostat hydrobromide; Trametinib dimethyl sulfoxideClinical stage IV cutaneous melanoma; Metastatic malignant neoplasm in the central nervous system; Metastatic melanoma; Pathologic stage IV cutaneous melanomaI/II (NCT04557956)
Tazemetostat; RituximabFollicular lymphomaII (NCT04762160)
Tafasitamab; Lenalidomide; Tazemetostat; Acalabrutinib; Daratumumab; Hyaluronidase-Fihj; Pomalidomide; DexamethasoneRelapsed/refractory hematologic malignanciesI/II (NCT05205252)
CPI-1205B-cell lymphomaI (NCT02395601)
CPI-1205; Enzalutamide; Abiraterone/prednisoneMetastatic castration-resistant prostate cancerI/II (NCT03480646)
Pyrotinib with capecitabine; AR inhibitor combined with everolimus or CDK4/6 inhibitor, or EZH2 inhibitorTriple-negative breast cancerI/II (NCT03805399)
SHR7390; Famitinib; SHR3162; Pyrotinib; Capecitabine; SHR1210; Everolimus; Nab paclitaxel; SHR2554; SHR3680; SHR6390; SHR1701; SERD; AI; VEGFiBreast cancerII (NCT04355858)

Future perspectives

Tumor immunotherapy has made tremendous advances, but there are still many obstacles in the way of achieving the larger social objective of “curing cancers.” Tumors, on the one hand, are inherently complex, adaptable, and heterogeneous. In contrast, immunotherapy primarily controls the tumor immune microenvironment rather than tumor cells. A complicated network of connections forms between tumor cells and distinct non-tumor cells, and there are many different impacting elements.

EZH2 plays a significant role in the control of immune and tumor cells by controlling their activation, activation, proliferation, and differentiation. Predicting clinical responses may be made easier with a thorough understanding of the pleiotropic effects of EZH2i on patients. Understanding the unique TME alterations brought on by EZH2i and the indication specificity it induces may also help to rationally combine immunotherapies. Similar to current immunotherapeutic approaches, EZH2i may have various impacts on the TME in terms of both the type of malignancy and the individual. When planning collaborative trials, this potential must be taken into account. In contrast to systemic injection of EZH2 inhibitors, which generally inhibit EZH2, targeted and tailored treatment targeting particular cell types with low toxicity is emerging. For instance, targeted EZH2 inhibitors and nanoparticles made of biomaterials, engineered medicinal materials, or chemical compounds can precisely control the expression of EZH2 in particular cell types. By focusing on EZH2, this strategy is anticipated to increase the impact of cancer immunotherapy. Additionally, there is developing data from the combined testing of EZH2i and ICB treatment, which may be used to inform the design of future combination therapies.

Therefore, it is essential to develop new anticancer therapy approaches targeting EZH2 in a range of human cancers. Future research concentrating on the immunoregulatory effects of EZH2 in tumors will give a platform for in-depth knowledge of the pathogenic processes of EZH2.

Conclusions

EZH2 plays a complex role in both promoting and inhibiting anti-tumor immune responses. On one hand, EZH2 is overexpressed in various cancers and promotes tumor growth by suppressing immune surveillance and enhancing immune evasion mechanisms. On the other hand, targeting EZH2 has been shown to enhance anti-tumor immune responses by increasing T cell infiltration, inducing immune checkpoint inhibitor expression, and promoting antigen presentation. Therefore, EZH2 inhibitors may have therapeutic potential as immunomodulatory agents for treating cancer patients by reprogramming the TME and enhancing anti-tumor immunity.

Abbreviations

AR: 

androgen receptor

ASCs: 

antibody secreting cells

CAR-T: 

chimeric antigen receptor T-cell

CTLA-4: 

cytotoxic T lymphocyte associated protein 4

DCs: 

dendritic cells

DN: 

double negative

EAF2: 

ELL associated factor 2

EZH2: 

enhancer of zeste homolog 2

EZH2i: 

EZH2 inhibitors

GLUT1: 

glucose transporter 1

H3K27: 

lysine 27 on histone 3

H3K27me3: 

trimethylation of lysine 27 of histone H3

HK2: 

hexokinase 2

ICB: 

immune checkpoint blockade

IRF: 

interferon regulatory factor

ISGs: 

interference stimulated genes

LAG-3: 

Lymphocyte activating gene-3

MHC: 

major histocompatibility complex

NK: 

natural kill cells

NSCLC: 

non-small cell lung cancer

OSCC: 

oral squamous cell carcinoma

PD-L1: 

programmed death ligand 1

PRC2: 

polycomb-repressive complex 2

PTEN: 

phosphatase and tensin homologue

RXRα: 

retinoid X receptor α

STAT3: 

signal transducer and activator of transcription 3

TAM: 

tumor associated macrophages

TCA: 

tricarboxylic acid cycle

TERT: 

telomerase reverse transcriptase

Tfh: 

T follicle helper cell

Th: 

T helper cell

TIM-3: 

T cell immunoglobulin and mucin domain-3

Tm: 

memory CD8+ T

TME: 

tumor microenvironment

Treg: 

T regulatory cell

YY1: 

Yin Yang-1

Declarations

Acknowledgement

None.

References

  1. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 2008;647(1-2):21-29 View Article PubMed/NCBI
  2. Wu K, Jiang Y, Zhou W, Zhang B, Li Y, Xie F, et al. Long Noncoding RNA RC3H2 Facilitates Cell Proliferation and Invasion by Targeting MicroRNA-101-3p/EZH2 Axis in OSCC. Mol Ther Nucleic Acids 2020;20:97-110 View Article PubMed/NCBI
  3. Cao W, Feng Z, Cui Z, Zhang C, Sun Z, Mao L, et al. Up-regulation of enhancer of zeste homolog 2 is associated positively with cyclin D1 overexpression and poor clinical outcome in head and neck squamous cell carcinoma. Cancer 2012;118(11):2858-2871 View Article PubMed/NCBI
  4. Cao W, Younis RH, Li J, Chen H, Xia R, Mao L, et al. EZH2 promotes malignant phenotypes and is a predictor of oral cancer development in patients with oral leukoplakia. Cancer Prev Res (Phila) 2011;4(11):1816-1824 View Article PubMed/NCBI
  5. Zhang L, Qu J, Qi Y, Duan Y, Huang YW, Zhou Z, et al. EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation. Nat Commun 2022;13(1):2543 View Article PubMed/NCBI
  6. Yi Y, Li Y, Li C, Wu L, Zhao D, Li F, et al. Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer. Oncogene 2022;41(11):1610-1621 View Article PubMed/NCBI
  7. Vantaku V, Putluri V, Bader DA, Maity S, Ma J, Arnold JM, et al. Correction: Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression. Oncogene 2020;39(40):6387-6392 View Article PubMed/NCBI
  8. Yu J, Yang K, Zheng J, Zhao P, Xia J, Sun X, et al. Activation of FXR and inhibition of EZH2 synergistically inhibit colorectal cancer through cooperatively accelerating FXR nuclear location and upregulating CDX2 expression. Cell Death Dis 2022;13(4):388 View Article PubMed/NCBI
  9. Cao W, Ribeiro Rde O, Liu D, Saintigny P, Xia R, Xue Y, et al. EZH2 promotes malignant behaviors via cell cycle dysregulation and its mRNA level associates with prognosis of patient with non-small cell lung cancer. PLoS One 2012;7(12):e52984 View Article PubMed/NCBI
  10. Hu FF, Chen H, Duan Y, Lan B, Liu CJ, Hu H, et al. CBX2 and EZH2 cooperatively promote the growth and metastasis of lung adenocarcinoma. Mol Ther Nucleic Acids 2022;27:670-684 View Article PubMed/NCBI
  11. April-Monn SL, Andreasi V, Schiavo Lena M, Sadowski MC, Kim-Fuchs C, Buri MC, et al. EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs). Cancers (Basel) 2021;13(19):5014 View Article PubMed/NCBI
  12. Emran AA, Fisher DE. Dual Targeting with EZH2 Inhibitor and STING Agonist to Treat Melanoma. J Invest Dermatol 2022;142(4):1004-1006 View Article PubMed/NCBI
  13. Lue JK, Amengual JE. Emerging EZH2 Inhibitors and Their Application in Lymphoma. Curr Hematol Malig Rep 2018;13(5):369-382 View Article PubMed/NCBI
  14. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010;42(2):181-185 View Article PubMed/NCBI
  15. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A 2010;107(49):20980-20985 View Article PubMed/NCBI
  16. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010;42(8):722-726 View Article PubMed/NCBI
  17. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tönnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010;42(8):665-667 View Article PubMed/NCBI
  18. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 2012;18(2):298-301 View Article PubMed/NCBI
  19. Wang X, Cao W, Zhang J, Yan M, Xu Q, Wu X, et al. A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination. EMBO J 2017;36(9):1243-1260 View Article PubMed/NCBI
  20. Wang X, Brea LT, Yu J. Immune modulatory functions of EZH2 in the tumor microenvironment: implications in cancer immunotherapy. Am J Clin Exp Urol 2019;7(2):85-91 PubMed/NCBI
  21. Zhang T, Gong Y, Meng H, Li C, Xue L. Symphony of epigenetic and metabolic regulation-interaction between the histone methyltransferase EZH2 and metabolism of tumor. Clin Epigenetics 2020;12(1):72 View Article PubMed/NCBI
  22. Shao FF, Chen BJ, Wu GQ. The functions of EZH2 in immune cells: Principles for novel immunotherapies. J Leukoc Biol 2021;110(1):77-87 View Article PubMed/NCBI
  23. Sun S, Yu F, Xu D, Zheng H, Li M. EZH2, a prominent orchestrator of genetic and epigenetic regulation of solid tumor microenvironment and immunotherapy. Biochim Biophys Acta Rev Cancer 2022;1877(2):188700 View Article PubMed/NCBI
  24. Wolchok J. Putting the Immunologic Brakes on Cancer. Cell 2018;175(6):1452-1454 View Article PubMed/NCBI
  25. Starzer AM, Preusser M, Berghoff AS. Immune escape mechanisms and therapeutic approaches in cancer: the cancer-immunity cycle. Ther Adv Med Oncol 2022;14:17588359221096219 View Article PubMed/NCBI
  26. Gong X, Karchin R. Pan-Cancer HLA Gene-Mediated Tumor Immunogenicity and Immune Evasion. Mol Cancer Res 2022;20(8):1272-1283 View Article PubMed/NCBI
  27. Ting Koh Y, Luz García-Hernández M, Martin Kast W. Cancer Drug Resistance. Totowa (NJ): Humana Press; 2006, 577-602 View Article
  28. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017;168(4):707-723 View Article PubMed/NCBI
  29. Benboubker V, Boivin F, Dalle S, Caramel J. Cancer Cell Phenotype Plasticity as a Driver of Immune Escape in Melanoma. Front Immunol 2022;13:873116 View Article PubMed/NCBI
  30. Hegde PS, Karanikas V, Evers S. The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition. Clin Cancer Res 2016;22(8):1865-1874 View Article PubMed/NCBI
  31. Guerrouahen BS, Maccalli C, Cugno C, Rutella S, Akporiaye ET. Reverting Immune Suppression to Enhance Cancer Immunotherapy. Front Oncol 2019;9:1554 View Article PubMed/NCBI
  32. Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol 2020;13(1):104 View Article PubMed/NCBI
  33. Kang N, Eccleston M, Clermont PL, Latarani M, Male DK, Wang Y, et al. EZH2 inhibition: a promising strategy to prevent cancer immune editing. Epigenomics 2020;12(16):1457-1476 View Article PubMed/NCBI
  34. Eich ML, Athar M, Ferguson JE, Varambally S. EZH2-Targeted Therapies in Cancer: Hype or a Reality. Cancer Res 2020;80(24):5449-5458 View Article PubMed/NCBI
  35. Cardoso C, Mignon C, Hetet G, Grandchamps B, Fontes M, Colleaux L. The human EZH2 gene: genomic organisation and revised mapping in 7q35 within the critical region for malignant myeloid disorders. Eur J Hum Genet 2000;8(3):174-180 View Article PubMed/NCBI
  36. Laible G, Wolf A, Dorn R, Reuter G, Nislow C, Lebersorger A, et al. Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J 1997;16(11):3219-3232 View Article PubMed/NCBI
  37. Tan JZ, Yan Y, Wang XX, Jiang Y, Xu HE. EZH2: biology, disease, and structure-based drug discovery. Acta Pharmacol Sin 2014;35(2):161-174 View Article PubMed/NCBI
  38. Du J, Li L, Ou Z, Kong C, Zhang Y, Dong Z, et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res Treat 2012;131(1):65-73 View Article PubMed/NCBI
  39. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008;27(58):7274-7284 View Article PubMed/NCBI
  40. Xu Z, Sun Y, Guo Y, Qin G, Mu S, Fan R, et al. NF-YA promotes invasion and angiogenesis by upregulating EZH2-STAT3 signaling in human melanoma cells. Oncol Rep 2016;35(6):3630-3638 View Article PubMed/NCBI
  41. He A, Shen X, Ma Q, Cao J, von Gise A, Zhou P, et al. PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev 2012;26(1):37-42 View Article PubMed/NCBI
  42. Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell 2012;48(4):572-586 View Article PubMed/NCBI
  43. Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol Cell 2011;43(5):798-810 View Article PubMed/NCBI
  44. Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 2012;338(6113):1465-1469 View Article PubMed/NCBI
  45. Jancewicz I, Szarkowska J, Konopinski R, Stachowiak M, Swiatek M, Blachnio K, et al. PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4(+) T Cells. Cancers (Basel) 2021;13(16):4148 View Article PubMed/NCBI
  46. Morel KL, Sheahan AV, Burkhart DL, Baca SC, Boufaied N, Liu Y, et al. EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat Cancer 2021;2(4):444-456 View Article PubMed/NCBI
  47. Goswami S, Apostolou I, Zhang J, Skepner J, Anandhan S, Zhang X, et al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest 2018;128(9):3813-3818 View Article PubMed/NCBI
  48. Bugide S, Green MR, Wajapeyee N. Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells. Proc Natl Acad Sci U S A 2018;115(15):E3509-E3518 View Article PubMed/NCBI
  49. Zingg D, Arenas-Ramirez N, Sahin D, Rosalia RA, Antunes AT, Haeusel J, et al. The Histone Methyltransferase Ezh2 Controls Mechanisms of Adaptive Resistance to Tumor Immunotherapy. Cell Rep 2017;20(4):854-867 View Article PubMed/NCBI
  50. Chen X, Cao G, Wu J, Wang X, Pan Z, Gao J, et al. The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection. Cell Mol Immunol 2020;17(3):247-260 View Article PubMed/NCBI
  51. Li Z, Duan Y, Ke Q, Wang M, Cen H, Zhu X. Gene set-based identification of two immune subtypes of diffuse large B cell lymphoma for guiding immune checkpoint blocking therapy. Front Genet 2022;13:1000460 View Article PubMed/NCBI
  52. Rai S, Inoue H, Sakai K, Hanamoto H, Matsuda M, Maeda Y, et al. Decreased expression of T-cell-associated immune markers predicts poor prognosis in patients with follicular lymphoma. Cancer Sci 2022;113(2):660-673 View Article PubMed/NCBI
  53. Hernández-Verdin I, Kirasic E, Wienand K, Mokhtari K, Eimer S, Loiseau H, et al. Molecular and clinical diversity in primary central nervous system lymphoma. Ann Oncol 2023;34(2):186-199 View Article PubMed/NCBI
  54. Versemann L, Patil S, Steuber B, Zhang Z, Kopp W, Krawczyk HE, et al. TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer. Cancers (Basel) 2022;14(14):3451 View Article PubMed/NCBI
  55. Du L, Fakih MG, Rosen ST, Chen Y. SUMOylation of E2F1 Regulates Expression of EZH2. Cancer Res 2020;80(19):4212-4223 View Article PubMed/NCBI
  56. Hou S, Clement RL, Diallo A, Blazar BR, Rudensky AY, Sharpe AH, et al. FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program. J Exp Med 2019;216(3):605-620 View Article PubMed/NCBI
  57. Böttcher M, Bruns H, Völkl S, Lu J, Chartomatsidou E, Papakonstantinou N, et al. Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis. J Immunother Cancer 2021;9(4):e001889 View Article PubMed/NCBI
  58. Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, et al. EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res 2012;72(1):315-324 View Article PubMed/NCBI
  59. Chien YC, Liu LC, Ye HY, Wu JY, Yu YL. EZH2 promotes migration and invasion of triple-negative breast cancer cells via regulating TIMP2-MMP-2/-9 pathway. Am J Cancer Res 2018;8(3):422-434 PubMed/NCBI
  60. Shin YJ, Kim JH. The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One 2012;7(1):e30393 View Article PubMed/NCBI
  61. Geng J, Li X, Zhou Z, Wu CL, Dai M, Bai X. EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer. Cancer Lett 2015;359(2):275-287 View Article PubMed/NCBI
  62. Toyokawa G, Takada K, Tagawa T, Hamamoto R, Yamada Y, Shimokawa M, et al. A Positive Correlation Between the EZH2 and PD-L1 Expression in Resected Lung Adenocarcinomas. Ann Thorac Surg 2019;107(2):393-400 View Article PubMed/NCBI
  63. Xiao G, Jin LL, Liu CQ, Wang YC, Meng YM, Zhou ZG, et al. EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma. J Immunother Cancer 2019;7(1):300 View Article PubMed/NCBI
  64. Chen X, Pan X, Zhang W, Guo H, Cheng S, He Q, et al. Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses. Acta Pharm Sin B 2020;10(5):723-733 View Article PubMed/NCBI
  65. Zhao Y, Wang XX, Wu W, Long H, Huang J, Wang Z, et al. EZH2 regulates PD-L1 expression via HIF-1α in non-small cell lung cancer cells. Biochem Biophys Res Commun 2019;517(2):201-209 View Article PubMed/NCBI
  66. Zhang L, Tian S, Pei M, Zhao M, Wang L, Jiang Y, et al. Crosstalk between histone modification and DNA methylation orchestrates the epigenetic regulation of the costimulatory factors, Tim-3 and galectin-9, in cervical cancer. Oncol Rep 2019;42(6):2655-2669 View Article PubMed/NCBI
  67. Wu X, Gu Z, Chen Y, Chen B, Chen W, Weng L, et al. Application of PD-1 Blockade in Cancer Immunotherapy. Comput Struct Biotechnol J 2019;17:661-674 View Article PubMed/NCBI
  68. Piunti A, Meghani K, Yu Y, Robertson AG, Podojil JR, McLaughlin KA, et al. Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma. Sci Adv 2022;8(40):eabo8043 View Article PubMed/NCBI
  69. Truax AD, Thakkar M, Greer SF. Dysregulated recruitment of the histone methyltransferase EZH2 to the class II transactivator (CIITA) promoter IV in breast cancer cells. PLoS One 2012;7(4):e36013 View Article PubMed/NCBI
  70. Ennishi D, Takata K, Béguelin W, Duns G, Mottok A, Farinha P, et al. Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition. Cancer Discov 2019;9(4):546-563 View Article PubMed/NCBI
  71. Burr ML, Sparbier CE, Chan KL, Chan YC, Kersbergen A, Lam EYN, et al. An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer Cell 2019;36(4):385-401.e8 View Article PubMed/NCBI
  72. Zhao L, Rao X, Huang C, Zheng R, Kong R, Chen Z, et al. Epigenetic reprogramming of carrier free photodynamic modulator to activate tumor immunotherapy by EZH2 inhibition. Biomaterials 2023;293:121952 View Article PubMed/NCBI
  73. Zhou L, Mudianto T, Ma X, Riley R, Uppaluri R. Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer. Clin Cancer Res 2020;26(1):290-300 View Article PubMed/NCBI
  74. Guo B, Tan X, Cen H. EZH2 is a negative prognostic biomarker associated with immunosuppression in hepatocellular carcinoma. PLoS One 2020;15(11):e0242191 View Article PubMed/NCBI
  75. Pang B, Zheng XR, Tian JX, Gao TH, Gu GY, Zhang R, et al. EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling. Oncotarget 2016;7(29):45134-45143 View Article PubMed/NCBI
  76. Sun CC, Zhu W, Li SJ, Hu W, Zhang J, Zhuo Y, et al. FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway. Genome Med 2020;12(1):77 View Article PubMed/NCBI
  77. Zheng M, Cao MX, Luo XJ, Li L, Wang K, Wang SS, et al. EZH2 promotes invasion and tumour glycolysis by regulating STAT3 and FoxO1 signalling in human OSCC cells. J Cell Mol Med 2019;23(10):6942-6954 View Article PubMed/NCBI
  78. Tao T, Chen M, Jiang R, Guan H, Huang Y, Su H, et al. Involvement of EZH2 in aerobic glycolysis of prostate cancer through miR-181b/HK2 axis. Oncol Rep 2017;37(3):1430-1436 View Article PubMed/NCBI
  79. Wang Y, Wang M, Wei W, Han D, Chen X, Hu Q, et al. Disruption of the EZH2/miRNA/β-catenin signaling suppresses aerobic glycolysis in glioma. Oncotarget 2016;7(31):49450-49458 View Article PubMed/NCBI
  80. Wang L, Jin Q, Lee JE, Su IH, Ge K. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc Natl Acad Sci U S A 2010;107(16):7317-7322 View Article PubMed/NCBI
  81. Wan D, Liu C, Sun Y, Wang W, Huang K, Zheng L. MacroH2A1.1 cooperates with EZH2 to promote adipogenesis by regulating Wnt signaling. J Mol Cell Biol 2017;9(4):325-337 View Article PubMed/NCBI
  82. Ringel AE, Drijvers JM, Baker GJ, Catozzi A, García-Cañaveras JC, Gassaway BM, et al. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell 2020;183(7):1848-1866.e26 View Article PubMed/NCBI
  83. Ahmad F, Patrick S, Sheikh T, Sharma V, Pathak P, Malgulwar PB, et al. Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma. J Neurochem 2017;143(6):671-683 View Article PubMed/NCBI
  84. Vella S, Gnani D, Crudele A, Ceccarelli S, De Stefanis C, Gaspari S, et al. EZH2 down-regulation exacerbates lipid accumulation and inflammation in in vitro and in vivo NAFLD. Int J Mol Sci 2013;14(12):24154-24168 View Article PubMed/NCBI
  85. Hayden A, Johnson PW, Packham G, Crabb SJ. S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res Treat 2011;127(1):109-119 View Article PubMed/NCBI
  86. Johnson MO, Siska PJ, Contreras DC, Rathmell JC. Nutrients and the microenvironment to feed a T cell army. Semin Immunol 2016;28(5):505-513 View Article PubMed/NCBI
  87. Li M, Melnick AM. An “EZ” Epigenetic Road to Leukemia Stem Cell Metabolic Reprogramming?. Cancer Discov 2019;9(9):1158-1160 View Article PubMed/NCBI
  88. Papathanassiu AE, Ko JH, Imprialou M, Bagnati M, Srivastava PK, Vu HA, et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat Commun 2017;8:16040 View Article PubMed/NCBI
  89. Gu Z, Liu Y, Cai F, Patrick M, Zmajkovic J, Cao H, et al. Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation. Cancer Discov 2019;9(9):1228-1247 View Article PubMed/NCBI
  90. Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 2019;25(5):825-837 View Article PubMed/NCBI
  91. Cormerais Y, Massard PA, Vucetic M, Giuliano S, Tambutté E, Durivault J, et al. The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). J Biol Chem 2018;293(8):2877-2887 View Article PubMed/NCBI
  92. Dann SG, Ryskin M, Barsotti AM, Golas J, Shi C, Miranda M, et al. Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2. EMBO J 2015;34(13):1773-1785 View Article PubMed/NCBI
  93. Li Y, Goldberg EM, Chen X, Xu X, McGuire JT, Leuzzi G, et al. Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas. Mol Cell 2022;82(20):3901-3918.e7 View Article PubMed/NCBI
  94. Mochizuki-Kashio M, Mishima Y, Miyagi S, Negishi M, Saraya A, Konuma T, et al. Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 2011;118(25):6553-6561 View Article PubMed/NCBI
  95. Cordero FJ, Huang Z, Grenier C, He X, Hu G, McLendon RE, et al. Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG. Mol Cancer Res 2017;15(9):1243-1254 View Article PubMed/NCBI
  96. Xie H, Xu J, Hsu JH, Nguyen M, Fujiwara Y, Peng C, et al. Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 2014;14(1):68-80 View Article PubMed/NCBI
  97. Lee SC, Miller S, Hyland C, Kauppi M, Lebois M, Di Rago L, et al. Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis. Blood 2015;126(2):167-175 View Article PubMed/NCBI
  98. Jacobsen JA, Woodard J, Mandal M, Clark MR, Bartom ET, Sigvardsson M, et al. EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints. J Immunol 2017;198(12):4682-4691 View Article PubMed/NCBI
  99. Wang C, Oshima M, Sato D, Matsui H, Kubota S, Aoyama K, et al. Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation. J Clin Invest 2018;128(9):3872-3886 View Article PubMed/NCBI
  100. Liu H, Li P, Wei Z, Zhang C, Xia M, Du Q, et al. Regulation of T cell differentiation and function by epigenetic modification enzymes. Semin Immunopathol 2019;41(3):315-326 View Article PubMed/NCBI
  101. Zhu J. T Helper Cell Differentiation, Heterogeneity, and Plasticity. Cold Spring Harb Perspect Biol 2018;10(10):a030338 View Article PubMed/NCBI
  102. Zhang Y, Kinkel S, Maksimovic J, Bandala-Sanchez E, Tanzer MC, Naselli G, et al. The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 2014;124(5):737-749 View Article PubMed/NCBI
  103. Hong J, Lee JH, Zhang Z, Wu Y, Yang M, Liao Y, et al. PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer. Cancer Res 2022;82(24):4624-4640 View Article PubMed/NCBI
  104. Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, et al. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity 2013;39(5):819-832 View Article PubMed/NCBI
  105. Yang XP, Jiang K, Hirahara K, Vahedi G, Afzali B, Sciume G, et al. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep 2015;5:10643 View Article PubMed/NCBI
  106. Xiao XY, Li YT, Jiang X, Ji X, Lu X, Yang B, et al. EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis. J Autoimmun 2020;108:102404 View Article PubMed/NCBI
  107. Yang Y, Liu K, Liu M, Zhang H, Guo M. EZH2: Its regulation and roles in immune disturbance of SLE. Front Pharmacol 2022;13:1002741 View Article PubMed/NCBI
  108. Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol 2012;8(6):337-347 View Article PubMed/NCBI
  109. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 2013;39(4):782-795 View Article PubMed/NCBI
  110. Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020;577(7791):549-555 View Article PubMed/NCBI
  111. Choi YS, Yang JA, Yusuf I, Johnston RJ, Greenbaum J, Peters B, et al. Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J Immunol 2013;190(8):4014-4026 View Article PubMed/NCBI
  112. Li F, Zeng Z, Xing S, Gullicksrud JA, Shan Q, Choi J, et al. Ezh2 programs T(FH) differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nat Commun 2018;9(1):5452 View Article PubMed/NCBI
  113. Cao W, Shen Q, Lim MY. Editorial: “Non-Coding RNAs in Head and Neck Squamous Cell Carcinoma”. Front Oncol 2021;11:785001 View Article PubMed/NCBI
  114. Cortez JT, Montauti E, Shifrut E, Gatchalian J, Zhang Y, Shaked O, et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature 2020;582(7812):416-420 View Article PubMed/NCBI
  115. Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, et al. Targeting the CBM complex causes T(reg) cells to prime tumours for immune checkpoint therapy. Nature 2019;570(7759):112-116 View Article PubMed/NCBI
  116. Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 2013;501(7466):252-256 View Article PubMed/NCBI
  117. Nakagawa H, Sido JM, Reyes EE, Kiers V, Cantor H, Kim HJ. Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity. Proc Natl Acad Sci U S A 2016;113(22):6248-6253 View Article PubMed/NCBI
  118. Kitagawa Y, Sakaguchi S. Molecular control of regulatory T cell development and function. Curr Opin Immunol 2017;49:64-70 View Article PubMed/NCBI
  119. Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, et al. Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer. Immunity 2016;45(5):1122-1134 View Article PubMed/NCBI
  120. Arvey A, van der Veeken J, Samstein RM, Feng Y, Stamatoyannopoulos JA, Rudensky AY. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol 2014;15(6):580-587 View Article PubMed/NCBI
  121. Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 2016;22(6):679-684 View Article PubMed/NCBI
  122. Wang D, Quiros J, Mahuron K, Pai CC, Ranzani V, Young A, et al. Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity. Cell Rep 2018;23(11):3262-3274 View Article PubMed/NCBI
  123. DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, et al. The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity 2015;42(2):227-238 View Article PubMed/NCBI
  124. De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, et al. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity 2016;45(5):1135-1147 View Article PubMed/NCBI
  125. Chang JT, Wherry EJ, Goldrath AW. Molecular regulation of effector and memory T cell differentiation. Nat Immunol 2014;15(12):1104-1115 View Article PubMed/NCBI
  126. Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 2012;12(11):749-761 View Article PubMed/NCBI
  127. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 2016;17(1):95-103 View Article PubMed/NCBI
  128. Eichenauer T, Simmendinger L, Fraune C, Mandelkow T, Blessin NC, Kluth M, et al. High level of EZH2 expression is linked to high density of CD8-positive T-lymphocytes and an aggressive phenotype in renal cell carcinoma. World J Urol 2021;39(2):481-490 View Article PubMed/NCBI
  129. Chen G, Subedi K, Chakraborty S, Sharov A, Lu J, Kim J, et al. Ezh2 Regulates Activation-Induced CD8(+) T Cell Cycle Progression via Repressing Cdkn2a and Cdkn1c Expression. Front Immunol 2018;9:549 View Article PubMed/NCBI
  130. Gray SM, Amezquita RA, Guan T, Kleinstein SH, Kaech SM. Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8(+) T Cell Terminal Differentiation and Loss of Multipotency. Immunity 2017;46(4):596-608 View Article PubMed/NCBI
  131. Yin J, Leavenworth JW, Li Y, Luo Q, Xie H, Liu X, et al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci U S A 2015;112(52):15988-15993 View Article PubMed/NCBI
  132. He S, Liu Y, Meng L, Sun H, Wang Y, Ji Y, et al. Ezh2 phosphorylation state determines its capacity to maintain CD8(+) T memory precursors for antitumor immunity. Nat Commun 2017;8(1):2125 View Article PubMed/NCBI
  133. Emran AA, Chatterjee A, Rodger EJ, Tiffen JC, Gallagher SJ, Eccles MR, et al. Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy. Trends Immunol 2019;40(4):328-344 View Article PubMed/NCBI
  134. Koss B, Shields BD, Taylor EM, Storey AJ, Byrum SD, Gies AJ, et al. Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion. Cancer Res 2020;80(21):4707-4719 View Article PubMed/NCBI
  135. Balkhi MY, Wittmann G, Xiong F, Junghans RP. YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells. iScience 2018;2:105-122 View Article PubMed/NCBI
  136. Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 2017;545(7655):452-456 View Article PubMed/NCBI
  137. Mizukami M, Hanagiri T, Yasuda M, Kuroda K, Shigematsu Y, Baba T, et al. Antitumor effect of antibody against a SEREX-defined antigen (UOEH-LC-1) on lung cancer xenotransplanted into severe combined immunodeficiency mice. Cancer Res 2007;67(17):8351-8357 View Article PubMed/NCBI
  138. Shi JY, Gao Q, Wang ZC, Zhou J, Wang XY, Min ZH, et al. Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin Cancer Res 2013;19(21):5994-6005 View Article PubMed/NCBI
  139. Kinoshita T, Muramatsu R, Fujita T, Nagumo H, Sakurai T, Noji S, et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. Ann Oncol 2016;27(11):2117-2123 View Article PubMed/NCBI
  140. Tokunaga R, Naseem M, Lo JH, Battaglin F, Soni S, Puccini A, et al. B cell and B cell-related pathways for novel cancer treatments. Cancer Treat Rev 2019;73:10-19 View Article PubMed/NCBI
  141. Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol 2003;4(2):124-131 View Article PubMed/NCBI
  142. Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013;23(5):677-692 View Article PubMed/NCBI
  143. Guo M, Price MJ, Patterson DG, Barwick BG, Haines RR, Kania AK, et al. EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production. J Immunol 2018;200(3):1039-1052 View Article PubMed/NCBI
  144. Mandal M, Powers SE, Maienschein-Cline M, Bartom ET, Hamel KM, Kee BL, et al. Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat Immunol 2011;12(12):1212-1220 View Article PubMed/NCBI
  145. Scharer CD, Barwick BG, Guo M, Bally APR, Boss JM. Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs. Nat Commun 2018;9(1):1698 View Article PubMed/NCBI
  146. Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest 2013;123(12):5009-5022 View Article PubMed/NCBI
  147. Herviou L, Jourdan M, Martinez AM, Cavalli G, Moreaux J. EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation. Leukemia 2019;33(8):2047-2060 View Article PubMed/NCBI
  148. Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, et al. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer Cell 2020;37(5):655-673.e11 View Article PubMed/NCBI
  149. Wei Y, Lao XM, Xiao X, Wang XY, Wu ZJ, Zeng QH, et al. Plasma Cell Polarization to the Immunoglobulin G Phenotype in Hepatocellular Carcinomas Involves Epigenetic Alterations and Promotes Hepatoma Progression in Mice. Gastroenterology 2019;156(6):1890-1904.e16 View Article PubMed/NCBI
  150. Li L, Li W, Wang C, Yan X, Wang Y, Niu C, et al. Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma. Cytotherapy 2018;20(1):134-148 View Article PubMed/NCBI
  151. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell 2018;172(5):1022-1037.e14 View Article PubMed/NCBI
  152. Noman MZ, Berchem G, Janji B. Targeting autophagy blocks melanoma growth by bringing natural killer cells to the tumor battlefield. Autophagy 2018;14(4):730-732 View Article PubMed/NCBI
  153. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008;28(4):571-580 View Article PubMed/NCBI
  154. Zhong J, Yang X, Chen J, He K, Gao X, Wu X, et al. Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands. Nat Commun 2022;13(1):4795 View Article PubMed/NCBI
  155. Ramakrishnan S, Granger V, Rak M, Hu Q, Attwood K, Aquila L, et al. Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer. Cell Death Differ 2019;26(10):2100-2114 View Article PubMed/NCBI
  156. Lin SJ, Chou FJ, Li L, Lin CY, Yeh S, Chang C. Natural killer cells suppress enzalutamide resistance and cell invasion in the castration resistant prostate cancer via targeting the androgen receptor splicing variant 7 (ARv7). Cancer Lett 2017;398:62-69 View Article PubMed/NCBI
  157. Arenas-Ramirez N, Sahin D, Boyman O. Epigenetic mechanisms of tumor resistance to immunotherapy. Cell Mol Life Sci 2018;75(22):4163-4176 View Article PubMed/NCBI
  158. Tiffen J, Gallagher SJ, Filipp F, Gunatilake D, Emran AA, Cullinane C, et al. EZH2 Cooperates with DNA Methylation to Downregulate Key Tumor Suppressors and IFN Gene Signatures in Melanoma. J Invest Dermatol 2020;140(12):2442-2454.e5 View Article PubMed/NCBI
  159. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 2006;25(3):315-322 View Article PubMed/NCBI
  160. Pathria P, Louis TL, Varner JA. Targeting Tumor-Associated Macrophages in Cancer. Trends Immunol 2019;40(4):310-327 View Article PubMed/NCBI
  161. Qi B, Yang C, Zhu Z, Chen H. EZH2-Inhibited MicroRNA-454-3p Promotes M2 Macrophage Polarization in Glioma. Front Cell Dev Biol 2020;8:574940 View Article PubMed/NCBI
  162. Saha D, Martuza RL, Rabkin SD. Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. Cancer Cell 2017;32(2):253-267.e5 View Article PubMed/NCBI
  163. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 2016;19(1):20-27 View Article PubMed/NCBI
  164. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008;8(12):958-969 View Article PubMed/NCBI
  165. Yin Y, Qiu S, Li X, Huang B, Xu Y, Peng Y. EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment. J Neuroinflammation 2017;14(1):220 View Article PubMed/NCBI
  166. Qiu S, Huang D, Yin D, Li F, Li X, Kung HF, et al. Suppression of tumorigenicity by microRNA-138 through inhibition of EZH2-CDK4/6-pRb-E2F1 signal loop in glioblastoma multiforme. Biochim Biophys Acta 2013;1832(10):1697-1707 View Article PubMed/NCBI
  167. Xu Y, Liao C, Liu R, Liu J, Chen Z, Zhao H, et al. IRGM promotes glioma M2 macrophage polarization through p62/TRAF6/NF-κB pathway mediated IL-8 production. Cell Biol Int 2019;43(2):125-135 View Article PubMed/NCBI
  168. Lu J, Xu Z, Duan H, Ji H, Zhen Z, Li B, et al. Tumor-associated macrophage interleukin-β promotes glycerol-3-phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells. Cancer Sci 2020;111(6):1979-1990 View Article PubMed/NCBI
  169. Zheng Y, Wang Z, Wei S, Liu Z, Chen G. Epigenetic silencing of chemokine CCL2 represses macrophage infiltration to potentiate tumor development in small cell lung cancer. Cancer Lett 2021;499:148-163 View Article PubMed/NCBI
  170. Xia L, Zhu X, Zhang L, Xu Y, Chen G, Luo J. EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer. Biotechnol Appl Biochem 2020;67(6):1011-1019 View Article PubMed/NCBI
  171. Zhao J, Li H, Zhao S, Wang E, Zhu J, Feng D, et al. Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling. Mol Cancer 2021;20(1):46 View Article PubMed/NCBI
  172. Su Y, Song X, Teng J, Zhou X, Dong Z, Li P, et al. Mesenchymal stem cells-derived extracellular vesicles carrying microRNA-17 inhibits macrophage apoptosis in lipopolysaccharide-induced sepsis. Int Immunopharmacol 2021;95:107408 View Article PubMed/NCBI
  173. Gunawan M, Venkatesan N, Loh JT, Wong JF, Berger H, Neo WH, et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol 2015;16(5):505-516 View Article PubMed/NCBI
  174. Wang Y, Wang Q, Wang B, Gu Y, Yu H, Yang W, et al. Inhibition of EZH2 ameliorates bacteria-induced liver injury by repressing RUNX1 in dendritic cells. Cell Death Dis 2020;11(11):1024 View Article PubMed/NCBI
  175. Wang Q, Zheng J, Zou JX, Xu J, Han F, Xiang S, et al. S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis. Chem Biol Interact 2020;317:108965 View Article PubMed/NCBI
  176. Zerif E, Khan FU, Raki AA, Lullier V, Gris D, Dupuis G, et al. Elucidating the Role of Ezh2 in Tolerogenic Function of NOD Bone Marrow-Derived Dendritic Cells Expressing Constitutively Active Stat5b. Int J Mol Sci 2020;21(18):6453 View Article PubMed/NCBI
  177. Doñas C, Carrasco M, Fritz M, Prado C, Tejón G, Osorio-Barrios F, et al. The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. J Autoimmun 2016;75:105-117 View Article PubMed/NCBI
  178. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015;527(7577):249-253 View Article PubMed/NCBI
  179. Hamaidia M, Gazon H, Hoyos C, Hoffmann GB, Louis R, Duysinx B, et al. Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism. JCI Insight 2019;4(18):128474 View Article PubMed/NCBI
  180. Kailayangiri S, Altvater B, Lesch S, Balbach S, Göttlich C, Kühnemundt J, et al. EZH2 Inhibition in Ewing Sarcoma Upregulates G(D2) Expression for Targeting with Gene-Modified T Cells. Mol Ther 2019;27(5):933-946 View Article PubMed/NCBI
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  • Cancer Screening and Prevention
  • pISSN 2993-6314
  • eISSN 2835-3315

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The Heightened Importance of EZH2 in Cancer Immunotherapy

Xiao-Hu Lin, Wen-Kai Zhou, Cheng-Zhong Lin, Wei Cao
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