Page 43 - ARNM-3-1

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

of MHC-I APP genes exhibit both activating H3K4me3 production of IL-2, which is vital for T-cell expansion. 68,69
and repressive H3K27me3 histone modifications. This Upregulation of PD-L1 on DCs can inhibit T-cell activation
combination silences the basal expression of MHC-I and promote immune evasion. 52
58
and limits its upregulation in response to cytokines. Abnormal signaling pathways also contribute to
The repression of genes by PRC2 is attributed to the immune escape in cancer, such as aberrant WNT/β-
H3K27me3 mark, a modification catalyzed by EZH2. catenin signaling, which can prevent T-cell infiltration and
58
As demonstrated by Burr et al., treatment with EZH2 suppress immune activation through various mechanisms,
58
inhibitors greatly reduces H3K27me3 levels, resulting including the upregulation of PD-L1 in cancer stem cells.
70
in the transcriptional activation of previously repressed Accumulation of β-catenin following WNT activation
MHC-I genes. 58 triggers the transcription of downstream target genes,
Differentially methylated CpGs in promoter regions such as MYC, which is associated with poor immune cell
(within 3kb of the transcription start site) were analyzed infiltration when highly expressed. 71-73 In TNBC, MYC
to identify genes with unique, concordant gene expression is highly expressed and negatively correlates with the
across TNBC subtypes. Despite an overall decrease in expression of key MHC-I genes (e.g., BM2), impairing
1
methylation, M-subtype TNBC tumors showed increased antigen presentation. MYC can also epigenetically repress
74
methylation and decreased expression in genes involved STING, a gene involved in autonomous immune responses,
in IFN-γ signaling, immune checkpoint pathways leading to reduced production of chemokines (e.g., CCL5,
(CD274, LAG3, and TIGIT), and MHC-mediated antigen CXCL10, and CXCL11), decreased recruitment of TILs,
processing and presentation (NLRC5, CIITA, HLA-A, and impaired T-cell-mediated immune surveillance. 52,71
HLA-B, and TAP1). This subtype exhibited extensive β-catenin activates the transcriptional repressor ATF3,
1
hypermethylation in regions associated with immune which inhibits CCL4 transcription and subsequently the
+
signaling (such as IFN-γ signaling, IFN-γ response, activation of CD103 DCs, diminishing the activation and
T lymphocyte differentiation, TNF response, and infiltration of CD8 T cells and reducing the effectiveness
+
immune cytokine signaling) and antigen processing and of ICIs. 52,75-77
presentation. Furthermore, EZH2 targets were found to be The JAK-STAT pathway, activated by IFNs, plays
1
suppressed in these hypermethylated regions, suggesting a significant role in enhancing MHC expression on
the potential deregulation of PRC2. 1 APCs, which is crucial for T-cell activation. However,
78
4.2. T-cell activation prolonged exposure to IFN-γ can exert selective pressure
on tumors, resulting in the downregulation of components
Recruitment and activation of antigen-presenting cells of the IFN-γ signaling pathway and facilitating immune
(APCs), such as dendritic cells (DCs) and macrophages, are evasion. 52,79 Furthermore, the loss of phosphatase and
essential for initiating immune responses. Cancer cells can tensin homolog (PTEN) has been associated with
promote immune escape by downregulating chemokines decreased T-cell recruitment and function, contributing to
that recruit APCs and inhibiting the danger signals that resistance against ICIs. PTEN is a critical regulator of the
80
activate them. For example, tumor-derived prostaglandin PI3K/Akt signaling pathway, which is essential for T-cell
52
+
E2 can disrupt CD8 T-cell responses, facilitating differentiation and function. The loss of PTEN leads
81
immune evasion. In addition, tumors can evade APC to enhanced PI3K/Akt signaling, negatively impacting
59
phagocytosis by upregulating “don’t eat me” signals, such T-cell persistence and expansion within the TME.
82
as CD47, whereas downregulating “eat me” signals, such as This dysregulation can result in an immunosuppressive
calreticulin (CRT). 60-62 In TNBC, glycosylation of B7-H4 environment that hinders effective anti-tumor immunity.
stabilizes its expression, inhibiting CRT surface expression
and allowing the tumor to escape immune destruction. 63 4.3. Programmed cell death ligand 1 expression
The maturation of DCs is marked by the upregulation of ICIs restore anti-tumor immunity by blocking the
costimulatory molecules, such as CD80, CD86, and CD40, PD1/PD-L1 signaling axis, reactivating exhausted T
52
which enables effective stimulation of T-cell proliferation cells in the TME. PD-L1 expression can be regulated in
and differentiation. 64,65 DCs have been observed to express five ways: (i) Chromatin changes, (ii) genomic changes,
high levels of PD-L1 whereas downregulating CD80 (iii) transcription factors and post-transcriptional
expression. This alteration prevents the activation of T cells regulation, (iv) translation and post-translational regulation,
through CD28, contributing to the reduced effectiveness and (v) induction within the TME. First, the CD274
52
of ICIs. 52,66,67 The interaction of CD80 and CD86 with gene, which encodes PD-L1, is located on chromosome
CD28 on T cells is important for T-cell priming and the 9p24.1, and alterations in chromatin structure and

Volume 3 Issue 1 (2025) 35 doi: 10.36922/arnm.5132