Page 42 - ARNM-3-1

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

expression in CD8 T cells through glycolysis restriction, the loss of TSAs, deficiencies in antigen presentation,
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which reduces the T-cell-mediated anti-tumor efficacy. 39,48 and failure to initiate effective immune responses, which
Regulatory T cells (Tregs), identified as CD4 , CD25 , collectively hinder the efficacy of immunotherapeutic
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and, FOXP3 T cells, function to suppress inflammation agents. 52,53 TNBC generates a greater number of neoantigens
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and activation of other effector T cells (Teffs). In Tregs, due to its high mutational burden and genome instability
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EZH2 forms a complex with the FOXP3 transcription compared to other breast cancer subtypes. The TME of
factor to maintain their activation state. Inhibiting EZH2 TNBC typically exhibits a high density of TILs, and PD-L1
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in Tregs leads to unstable FOXP3 expression, granting is commonly overexpressed in TNBC relative to other
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Tregs pro-inflammatory properties, promoting the breast cancer subtypes. The multicenter, non-randomized
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recruitment of CD4 and CD8 T cells, and increasing the Phase Ib trial KEYNOTE-012 showed an overall response
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production of IFN-γ and TNF-α, which enhances effective rate (ORR) of <20% in advanced PD-L1-expressing
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anti-tumor immunity. 39 TNBC treated with pembrolizumab. Conversely, the
KEYNOTE-086 trial observed significantly higher ORRs
Natural killer cells express various cytokine receptors and disease control rates in TNBC tumors with higher levels
linked to chemotaxis and activation, allowing them to be of TILs when treated with pembrolizumab. This suggests
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recruited to the tumor site, where they are activated by that the presence of TILs is a critical factor influencing
cytokines, such as IL-12, to exert anti-tumor effects. 39,49 the success of immunotherapy in advanced TNBC.
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EZH2-expressing tumor cells exhibit decreased expression Furthermore, alterations in MHC-1 expression, often due
of the NKG2D ligand, which hinders NK cell activation to downregulation or structural modifications, facilitate
and directly inhibits NK cell maturation and function. immune escape by impairing antigen presentation.
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Inhibiting EZH2 increases NK cell numbers, promotes their In TNBC patients resistant to ICIs, downregulation
terminal maturation, and enhances their cytotoxicity. 39 of human leukocyte antigen class 1 (HLA-1) has been
There are two main phenotypes of myeloid-derived frequently observed, potentially linked to mutations in
suppressor cells (MDSCs): Monocytic MDSCs and HLA-1 encoding genes and the beta-2-microglobulin
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polymorphonuclear MDSCs. In tumors, monocytic gene. Transcription factors, such as NF-κB and NLRC5,
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MDSCs, such as monocytes, quickly differentiate into along with various epigenetic mechanisms, play pivotal
tumor-associated macrophages. EZH2-induced H3K27me3 roles in regulating HLA-1 expression, with their ablation
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reduces CCL2 expression and decreases macrophage significantly affecting antigen presentation. For instance,
infiltration, whereas EZH2 inhibition polarizes macrophages interferons (IFNs) can induce the expression of HLA-1
toward a more anti-tumor phenotype. Despite these effects, heavy chains and related components, whereas disruptions
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EZH2 inhibitors often yield unsatisfactory results in clinical in these pathways can lead to HLA-1 downregulation. In
trials. One suggested explanation is the accumulation of addition, TSAs arise from non-synonymous mutations,
MDSCs, which creates a more immune-suppressed TME gene fusion, and other genomic alterations, and stimulate
and weakens the anti-tumor effect, underscoring the T-cell-mediated adaptive immunity; their abundance
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importance of combination therapies. 39 correlates with the tumor mutational burden (TMB).
Patients with high TMB are generally more responsive to
Cancer-associated fibroblasts (CAFs) are stromal ICI treatment due to the increased abundance of TSAs;
components in the TME that facilitate tumor invasion and however, PD-L1 expression does not consistently correlate
metastasis by producing growth factors, cytokines, and with TMB across various cancer types. Epigenetic
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chemokines, that support cancer cell growth and create changes, such as high EZH2 levels, can result in silencing
an immunosuppressive microenvironment. The role of immune-related genes and facilitate immune escape by
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of EZH2 in CAFs is somewhat conflicting; while EZH2 downregulating the expression and presentation of tumor
inhibition can suppress angiogenesis, the reduction in antigens. 39,56,57
H3K27me3 levels in CAFs contributes to the maintenance
of cancer cell stemness and growth. 39 Highlighting the important role of cytotoxic T cells as
key effector cells in ICI-treated patients, mutations in genes
4. Immune escape and immunotherapy encoding components of the MHC-I antigen processing
resistance in TNBC pathway (APP) or the IFN-γ response pathway often result
in immunotherapy resistance. A genome-wide CRISPR/
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4.1. Tumor-specific antigens (TSAs) and MHC Cas9 screen has identified a function of PRC2 that
expression coordinates the transcriptional silencing of the MHC-I
In TNBC, several immune evasion mechanisms contribute APP, promoting evasion of T-cell-mediated immunity.
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to resistance to immunotherapy. These mechanisms include In cancers with low MHC-I expression, the promoters

Volume 3 Issue 1 (2025) 34 doi: 10.36922/arnm.5132