Page 37 - ARNM-3-1

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

1. Background a T-cell response. Table 1 lists key clinical studies of
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immunotherapy in ARID1A-deficient tumors.
Triple-negative breast cancer (TNBC) is defined by
the absence of estrogen receptor and progesterone Although the effectiveness of immune checkpoint
receptor expression, as well as the amplification of the inhibitors (ICIs) in breast cancer is less pronounced
human epithelial growth factor receptor 2. TNBC is than that seen in other tumor types, and most patients
a heterogeneous disease comprising subtypes such as with TNBC ultimately develop resistance to these
12
basal-like (BL1 and BL2), mesenchymal (M), and luminal agents, ARID1A-deficiency in TNBC has been shown
androgen receptors. Each TNBC subtype is associated to increase chromatin accessibility and gene expression
1
with different transcriptional patterns and immune cell of nucleophosmin 1, which in turn further activates
compositions. Notably, M-subtype tumors exhibit high PD-L1 transcription. Elevated PD-L1 levels could
13
mutational loads, genomic instability, lack of immune cells, render this subgroup more responsive to ICIs; however,
low programmed cell death ligand 1 (PD-L1) expression, ARID1A deficiency was also found to inhibit CD8 T cells,
+
decreased global DNA methylation, and transcriptional contributing to adaptive immune resistance in TNBC.
13
repression of genes responsible for antigen presentation. Using xenograft models, Chen et al. demonstrated that
1
13
The presence of immune cells has been associated with TNBC with low ARID1A expression-induced PD-L1
survival; tumors with fewer immune cells have displayed elevation was associated with reduced tumor volume and
a trend toward shorter progression-free intervals, whereas pulmonary metastasis when treated with atezolizumab
tumors with greater stromal immune cells have shown (anti-PD-L1), compared to ARID1A-high TNBC.
a lower risk of recurrence. Variations in immune cell This occurred despite insufficient anti-tumor immune
1-3
composition and genetic susceptibilities specific to different infiltrates, especially CD8 T cells. Notably, atezolizumab
+
13
subtypes indicate potential new treatment approaches for significantly increased the CD45 CD8 T-cell population
+
+
TNBC to enhance the efficacy of immunotherapy. For in the ARID1A-deficient tumors. Tumor tissues from
1
13
example, deletions of DNA repair genes and members patients with metastatic TNBC treated with pucotenlimab
of the BRG1-associated factors, SWItch/Sucrose Non- (anti-PD-1) with gemcitabine and cisplatin were analyzed
Fermentable (SWI/SNF) complex, are more commonly for ARID1A deficiency and PD-L1 expression as part of the
observed in M-subtype TNBC tumors. The SWI/SNF CTR20191353 clinical trial. Kaplan–Meier progression-
1
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complex regulates chromatin structure and is one of the free survival (PFS) analysis based on ARID1A and PD-L1
most frequently mutated protein complexes in human expression demonstrated that patients with low ARID1A
cancers. It has also been found that SWI/SNF has a role expression had significantly longer PFS. The longest PFS
4,5
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6
in regulating anti-tumor immunity. Research indicates observed was 615 days in the ARID1A-low/PD-L1-high
approximately 30% of breast tumors exhibit genetic subgroup. 13
alterations in one or more SWI/SNF subunits, such as the
AT-rich interactive domain 1A gene (ARID1A), and these Given these findings of PD-L1 elevation but low anti-
gain- and loss-of-function mutations are linked to the tumor immune infiltrates, exploration of combination
initiation and progression of cancer. Low expression levels therapies to further enhance the effects of ICIs in ARID1A-
4
of ARID1A are found in 78% of TNBCs and are associated deficient TNBC through immune stimulation is warranted.
with poor prognosis. The loss of ARID1A expression Therapeutic strategies for ARID1A-mutant breast
4,7
presents a challenge for therapeutic targeting, highlighting cancer include inhibition of enhancer of zeste homolog
4
the necessity to uncover therapeutic vulnerabilities in 2 (EZH2). EZH2 is an enzymatic catalytic subunit of
ARID1A-deficient tumors. ARID1A deficiency has been polycomb repressive complex 2 (PRC2), one of two main
6
shown to variably enhance PD-L1 expression, but the polycomb group complexes that mediate gene silencing
overall impact on immune cell populations can vary. While mainly through modulating chromatin structure. 14-16
ARID1A deficiency may promote an immune response, EZH2 induces trimethylation of lysine 27 of histone H3
17
it does not guarantee an increase in tumor-infiltrating (H3K27me3) and deposition of H3K27me3 at target genes
lymphocytes (TILs) across all tumor types. For example, signals for polycomb repressive complex 1 recruitment,
8,9
Sun et al. demonstrated increased infiltration of CD4 + which in turn enforces transcriptional silencing through
10
T cells and Th17 cells, along with enhanced CD8 effector compaction of chromatin. Targeting epigenetic regulators
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and antigen presentation signatures in ARID1A-deficient such as EZH2 may enhance tumor immunogenicity,
gastric cancer. Conversely, Jung et al. found that improve immune cell function, and modulate the
11
10
low ARID1A expression was associated with decreased immunosuppressive tumor microenvironment (TME)
CD8 T-cell infiltration in ovarian clear cell carcinoma, to synergize with immunotherapy. EZH2 contributes
19
suggesting that blocking PD-L1 is unlikely to result in to cancer progression through various mechanisms,
Volume 3 Issue 1 (2025) 29 doi: 10.36922/arnm.5132