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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,* 
Cancer Screening and Prevention   2023;2(2):117-129

doi: 10.14218/CSP.2023.00006

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Citation: Lin XH, Zhou WK, Lin CZ, Cao W. The Heightened Importance of EZH2 in Cancer Immunotherapy. Cancer Screen Prev. 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.

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