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Tumor Discovery Immune and epigenetic therapies for TNBC

Another potential target in TNBC is B7-H3, which such as indoleamine 2,3-dioxygenase 1 (IDO1) promoter
promotes a pro-vascularization state due to the increased hypomethylation and CTLA-4 DNA methylation changes,
expression on TAMs and cancer cells, resulting in a poorer play crucial roles in modulating immune responses,
prognosis. In TNBC mouse models, blocking PD-1 was highlighting the importance of integrating epigenetic
found to be more effective when combined with the therapies to optimize immunotherapeutic outcomes in
inhibition of this immunological receptor. Knockdown of TNBC.
B7-H3 in vitro made cells more susceptible to AKT/mTOR However, combination treatments present certain
inhibitors and reduced glycolytic activity. Disrupted difficulties, including drug interactions, adverse side
epigenetic processes that promote elevated B7-H3 effects, and patient adherence. Furthermore, according to
expression levels have been linked to cancer development Huang et al., HDAC1 in the HDAC family largely acts as
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in several studies. 9 a pro-cancer factor, whereas HDAC6 may have anticancer
3.2. Epigenetic implication to immune response and properties. To determine the best dosage regimens and
anti-tumor immunity enhancement in TNBC combinations of HDACis to maximize their therapeutic
advantages in cancer treatment, more investigation and
HDACs, a class of epigenetic enzymes, play a crucial role clinical studies are required.
in regulating the equilibrium of acetylation in proteins
and histones through lysine acetylation and deacetylation 4. The role of IDO1 in TNBC
processes, which are essential for carcinogenesis.
Carcinogenesis is aided by the dysregulation of HDAC Breast carcinomas frequently express IDO1, particularly in
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expression and activity in cancer, which results in triple-negative, basal-like breast tumors. IDO1 is a key
chromatin remodeling and changed expression of player in cancer immunotherapy, responsible for catalyzing
tumor suppressor genes. Inhibiting HDACs can induce the conversion of tryptophan (Trp) to kynurenine (Kyn).
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apoptosis from cell cycle arrest by releasing oncogenic According to Dill et al., IDO1 expression is highest in
+
transcription suppressors. Research has demonstrated TNBC. Approximately 70% of PD-L1 breast neoplasms
that HDACis decrease the number of tumor-associated express IDO1, while the majority of low PD-L1-expressing
cells, such as MDSCs, while increasing the production of breast neoplasms are negative for IDO1. Moreover,
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T-cell chemokines, thereby supporting enhanced T-cell Asghar et al. found that elevated IDO1 levels in BC are
infiltration into tumors. In addition, HDACis increase correlated with high COX-2 expression, with around 40%
+
the expression of immune checkpoint proteins PD-L1 and of HER2 breast tumors overexpress IDO1, suggesting the
PD-L2 and enhance the efficacy of immune checkpoint possibility of using synergistic therapeutic techniques that
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blockade therapies, such as PD-1 blockade, which suggests are comparable to those employed in TNBC.
the potential of combining HDACis with immunotherapy The role of IDO1 and its immune-suppressive effect in
to amplify the immunotherapeutic response. 99 TNBC cells was investigated by Jing et al., who showed
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However, the interaction between DNA methylation that high IDO1 levels impair the tumoricidal potential
and histone deacetylation might result in a self-reinforcing of local NK cells. Silencing or inhibiting IDO1 in TNBC
silencing mechanism, potentially compromising the cells significantly boosts IFN-γ production and enhances
effectiveness of monotherapy and leading to resistance. In the cytolytic activity of co-cultured NK cells. Furthermore,
humans, HDACis have been demonstrated to downregulate early-stage TNBC patients who test positive for PD-L1 have
the expression of DNMT1, a DNA methyltransferase, in significantly higher levels of IDO1 than PD-L1, indicating
BC cells. Furthermore, blocking HDAC3 can increase that IDO1 plays an important role in the low response
DNMT1’s acetylation level, reducing its stability. to anti-PD-L1 therapy and that it is an important target
Combining HDAC3 inhibition with DNMT1 inhibition for therapeutic modification of the immunosuppressive
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in multiple myeloma cell lines and patients has shown TME.
synergistic effects in generating DNMT1 downregulation, IDO1 activation is one mechanism by which tumors
growth inhibition, and death. This shows that there may evade antitumor immunity. Higher IDO1 mRNA expression
be synergistic benefits and improved BC outcomes when has been linked to basal-like BC in earlier research. IDO1
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DNMTis and HDACis are combined. Research indicates is more commonly expressed in ER tumors, particularly
-
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that HDACis can improve immune checkpoint blockade in the basal-like subtype, as opposed to the luminal
therapies by increasing T-cell infiltration and upregulating subtype, as demonstrated by Noonepalle et al. Using
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PD-L1 and PD-L2 expression, suggesting a synergistic matched 450K-methylation array data, they discovered
potential when combined with immunotherapy. In that differential IDO1 expression is linked to its promoter
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addition, as illustrated in Table 5, various epigenetic factors, methylation status, demonstrating an inverse relationship
Volume 3 Issue 3 (2024) 9 doi: 10.36922/td.3383