Page 41 - ARNM-3-1

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

of most breast cancer cells because total EZH2 protein
levels remain unaffected. This observation suggests that
the expression of the EZH2 protein itself, rather than
its methyltransferase activity, may be crucial for the
occurrence and development of breast cancer, including
TNBC. Therefore, designing degradation molecules
42
that selectively reduce EZH2 protein levels may offer an
effective treatment strategy for EZH2-dependent tumors
such as TNBC. MS1943, an EZH2 selective degrader,
42
has been shown to suppress TNBC tumor growth
in vivo. Combining enzymatic inhibition and depletion
43
or degradation of EZH2 is another potential strategy
for treating TNBC with high EZH2 expression. Mei
et al. showed that IHMT-337, an irreversible inhibitor
44
of EZH2, exerts its effects through covalent modification
of the EZH2 protein, leading to a sustained inhibition of
44
its methyltransferase activity. This inhibition results in
the downregulation of target genes associated with cell
proliferation and survival, particularly those involved in
regulating cyclin-dependent kinase 4 transcription, thus
highlighting the therapeutic potential of inhibiting both Figure 3. Enhancer of zeste homolog 2 (EZH2) immune effects. EZH2
catalytic and non-catalytic function of EZH2 through mainly reduces anti-tumor immune cell effects within the tumor
microenvironment. EZH2 restricts T helper (Th) subsets Th1, Th2,
protein degradation. IHMT-337 and EPZ6438 were and Th17, promotes T follicular (Tfh) differentiation and function, and
44
assessed for effects on TNBC cell line proliferation, and promotes CD4 T regulatory (Treg) stability and suppressive activity.
123
+
IHMT0337 was found to robustly suppress TNBC cell EZH2 promotes CD8 T memory (Tmem) precursors while reducing
+
123
+
growth, whereas EPZ6438 had little to no effect on cell CD8 T effector (Teff) function. EZH2 inhibits natural killer (NK) cells
123
44
proliferation. In pre-clinical models, both in vitro and and negatively regulates invariant natural killer T cells (iNKT). EZH2
maintains pro-inflammatory macrophage polarization and survival and
in vivo, IHMT-337 inhibited TNBC cell proliferation. potentially limits myeloid-derived suppressor cell (MDSC) formation.
44
123
Although inhibitors of methyltransferase activity of Created in BioRender by Lukas, L. (https://BioRender.com/o93d285).
EZH2, such as Tazemetostat, may not be as effective in
inhibiting TNBC cell proliferation, there remains merit in interferon-gamma (IFN-γ), tumor necrosis factor-alpha
investigating combination strategies. Mei et al. found that (TNF-α), and interleukin 2 (IL-2), to promote cytotoxic
44
residual H3K27me3 persists after knockout of endogenous T-cell and natural killer (NK) cell anti-tumor responses.
9,13
EZH2, supporting other reports that EZH1 can target EZH2-dependent gene silencing influences the effector
44
a subset of EZH2-regulated genes. This functional differentiation status of T helper cell subsets and CD8 T
45
+
redundancy allows EZH1 to partially compensate for the cells following antigen stimulation. Furthermore, EZH2
48
loss of EZH2. 46,47 Thus, combining an EZH2 inhibitor with activity inhibits the differentiation and function of NK cells,
an ICI may be a promising therapeutic strategy. 44 indicating that targeting EZH2 could enhance both adaptive
and innate cancer immunotherapy. 49
3. Immune effects of enhancer of zeste +
In CD4 T cells, EZH2 binds to genes encoding
homolog 2 the transcription factors T-bet, EOMES, and GATA3,
Epigenetic dysregulation can affect the TME, influencing restricting the differentiation and plasticity of T helper
immune cell composition, cytokine signaling, and expression (Th) cells. Loss of EZH2 results in increased Th1 and
39
of immune checkpoints, ultimately contributing to immune Th2 polarization and promotes T-cell infiltration by
39
evasion. EZH2 plays a pivotal role in modulating immune enhancing the expression of chemokines CXCL9 and
16
cells and tumor cells within the TME, as shown in Figure 3. CXCL10. EZH2 plays a crucial role in the formation
39
Anti-tumor immunity is driven by two main types of T cells: of CD8 T memory precursors by activating Id3 while
+
major histocompatibility complex class I (MHC-I)-restricted silencing Id2, EOMES, and PRDM1. 39,50 Although EZH2
CD8 cytotoxic T cells and MHC-II-restricted CD4 helper regulates the function and survival of effector CD8 T cells
+
+
+
T cells. CD8 T cells release cytotoxic molecules, such by repressing the transcription of NUMB and FBXW7
+
39
as granzyme B and perforin, to directly kill tumor cells, through increased H3K27me3 deposition – thereby
whereas CD4 T cells secrete various cytokines, including activating the Notch pathway – tumors can limit EZH2
+
Volume 3 Issue 1 (2025) 33 doi: 10.36922/arnm.5132