Page 44 - ARNM-3-1

Advances in Radiotherapy
& Nuclear Medicine EZH2 inhibition in ARID1A-deficient TNBC

accessibility can directly influence its expression. Second, the activation of CD28 signaling. For example, the anti-
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abnormal PD-L1 expression can arise from disruptions CTLA-4 antibody ipilimumab increases EZH2 expression
at any stage of the gene transcription and translation in peripheral CD4 T cells, suggesting that inhibiting
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process, where the abnormal activation or inactivation of EZH2 in T cells may enhance the effectiveness of anti-
signaling pathways can impact immune function. Third, CTLA-4 therapy. Pre-clinical studies have shown that
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the excessive secretion of pro-inflammatory cytokines, EZH2 inhibition can improve the anti-tumor efficacy of
such as IFN-γ, TNF-α, and interleukins in the TME, can ipilimumab in mice inoculated with bladder cancer and
induce PD-L1 expression in tumor cells through various melanoma. 39,90 Combining an EZH2 inhibitor with anti-
signaling pathways, facilitating immune escape. 52,83,84 CTLA-4, compared to anti-CTLA-4 monotherapy, reduced
EZH2 can upregulate immune checkpoints on cancer cells; the percentage of CD4 FoxP3 Tregs and increased the
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for example, EZH2 promotes hypoxia-inducible factor percentage of intratumoral CD4 ICOS T-bet and CD8
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1-alpha expression, which in turn upregulates PD-L1 in IFN-γ Teff cells in both bladder and melanoma models,
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lung cancer cells. 39,85 Several strategies have been proposed resulting in an increased ratio of Teffs to Tregs. As a
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to overcome drug resistance mechanisms in TNBC result of these findings, several EZH2 inhibitors, such as
that bypass effective PD-L1 blockade: enhancing tumor tazemetostat and CPI-1205, are currently being studied
immunogenicity, increasing antigen presentation by MHC, in clinical trials, either as single agents or in combination
and regulating the recruitment and infiltration of immune with immunotherapies for various cancers, including
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effector cells. These approaches aim to boost the presence clinical trials combining tazemetostat with pembrolizumab
of TILs within the tumor, thereby restoring anti-tumor for urothelial carcinoma. Zingg et al. found that
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immune responses. 52 subtoxic doses of EZH2 inhibitors could prevent immune
resistance during immunotherapy, demonstrating that
5. Combination therapy strategies in TNBC EZH2 inactivation synergizes with anti-CTLA-4 and IL-2
5.1. Enhancer of zeste homolog 2 inhibition and immunotherapy in melanoma pre-clinical models. 92
immunotherapy Integrative analyses of TNBC multi-omics by Lehmann
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The emerging field of epi-immunotherapy, which integrates et al. have identified characteristics of TNBC subtypes and
epigenetic and immune therapies, can potentially make subtype-specific genetic or pharmacologic vulnerabilities
TNBC more responsive to ICIs by remodeling a suppressive for future investigation. Pre-clinical data provide a strong
TME. In non-TNBC solid tumors, EZH2 inhibition has rationale for using EZH2-inhibitory agents to restore
been shown to enhance the response to immunotherapy. MHC-I expression in immune-cold, PD-L1-negative, and
EZH2 inhibition has been demonstrated to increase M-subtype tumors, which exhibit the lowest levels of cell
MHC-I expression and overcome anti-PD-1 resistance, surface MHC-I expression. MHC-I expression can be
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thereby suppressing tumor growth in a pre-clinical model epigenetically silenced by PRC2 and restored by EZH2
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of head and neck cancer. In addition, EZH2 inhibitors inhibitors in mesenchymal cancer cell lines. Chromatin
and CRISPR-mediated EZH2 deficiency enhanced antigen immunoprecipitation sequencing analysis following EZH2
presentation on tumor cells, promoted antigen-specific inhibition has shown that increased MHC-I expression
CD8 T-cell proliferation, increased IFN-γ production, and correlates with decreased promoter H3K27me3 occupancy
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improved tumor cell cytotoxicity. Furthermore, EZH2 at the MHC-I loci and the transactivator NLRC5. 1
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inhibition also increased PD-L1 expression on the surfaces Vejmelkova et al. assessed the therapeutic potential
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of hepatoma cells, improving the efficacy of anti-PD-L1 of Tazemetostat in treating pediatric malignant rhabdoid
therapy. In a pre-clinical model of non-small-cell lung tumors characterized by the loss of integrase interactor 1
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cancer, EZH2 inhibition increased the efficacy of anti-PD-1 (INI1) protein. In INI1-negative tumors, the loss of INI1
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by elevating double-stranded RNA levels and inducing leads to aberrant EZH2 activity, resulting in the silencing
IFN pathway stress-mediated anti-tumor immunity. 39,88 of tumor suppressor genes and promoting oncogenesis.
The inhibition of EZH2 has been shown to upregulate In this study, two patients received tazemetostat in
antigen presentation genes and PD-L1. Moreover, in an combination with immunotherapy. One patient with a
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immunocompetent Lewis lung carcinoma tumor model, rhabdoid tumor of the ovary received tazemetostat as
EZH2 inhibition caused tumor regression and enhanced maintenance following resection, chemotherapy, and
CD8 T cells activity. 40 radiotherapy, alongside immunotherapy (nivolumab),
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Cytotoxic T-lymphocyte-associated protein 4 achieving an event-free survival of 44 months. A second
(CTLA-4) blockade has been shown to increase EZH2 patient with relapsed atypical teratoid rhabdoid tumor
expression in T cells in both humans and mice due to underwent treatment consisting of metronomic therapy,

Volume 3 Issue 1 (2025) 36 doi: 10.36922/arnm.5132