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Tumor Discovery Immune and epigenetic therapies for TNBC

Class I. Table 4 summarizes various immunotherapy of control. To re-establish antitumor immunity, aberrant
9
treatments for TNBC, focusing on their mechanisms of epigenetic processes could potentially be rectified using
action and associated epigenetic mutations or targets. epigenetic drugs such as HDAC inhibitors (HDACis)
These treatments include monoclonal antibodies such as and DNMTis. These treatments contribute to the
pembrolizumab, atezolizumab, and nivolumab, which overexpression of several immunological checkpoint
target PD-L1 expression, as well as chimeric antigen proteins.
receptor T-cell therapies targeting tumor-specific antigens.
Apart from PD-1/PD-L1 and CTLA-4, there is
3.1. Epigenetic mechanisms underlying the increasing popularity of inhibitory receptors as possible
dysregulation of immune checkpoint molecules targets in immunotherapy. The impact of ICIs combined
Immune checkpoints can impede CTL immune response, with HDACis to improve immunotherapy responses
53
which can eliminate tumor cells once identified. The in TNBC in vivo was studied by Fattori et al. It was
strength and duration of the immune response are discovered that HDACi was responsible for increased
regulated by a variety of inhibitory mechanisms that are HLA-DR and PD-L1 expression in TNBC cells. This
part of ICs. By activating IC pathways, cancer cells can enhanced the inhibition response of PD-1/CTLA-4 in a
96
evade T-cell cytotoxicity within the TME. The most well- mouse model of TNBC, leading to tumor development
documented mechanisms of T-cells deactivation entail reduction and an improvement in survival. This effect was
+
+
the binding of CTLA-4 on T-cells to CD80/86 on antigen- linked to CD4 and FOXP3 T-cell’s downregulation as
presenting cells (APCs) and the binding of PD-1 on T-cells well as enhanced T-cell tumor infiltration. 53
to PD-L1 on cancer cells and APCs. 9 The tumor cell surface-expressed proteins CD155
In primary BC, various immune checkpoint proteins, and CD112 interact with the T-cell immunoglobulin and
including CTLA-4, TIM-3, and LAG-3, are upregulated ITIM domains (TIGIT) of the T-cell immunoreceptor on
+
+
through mechanisms such as DNA hypomethylation the membranes of NK, CD8 T-cells, and CD4 T-cells.
and decreased repressive histone marks (H3K27me3 and Following FOXP3 binding and promoter hypomethylation,
H3K9me3) in promoter regions. Regarding regulation of TIGIT is overexpressed, and metastatic BC has been shown
97
PD-L1, while DNA methylation influences its expression in to have higher levels of CD155 expression compared to
other malignancies, such as gastric cancer and melanoma, normal tissue. CD155 expression is associated with a
BC appears to exhibit full demethylation of PD-L1, with poorer prognosis in BC, highlighting its significance in
histone modifications serving as the primary mechanism novel therapeutics and outcome prediction. 98

Table 4. Immune therapy approaches and targets in triple‑negative breast cancer
Immunotherapy Mechanism of action Targets Notes References
Pembrolizumab Anti-PD-1 monoclonal PD-L1 expression Approved for TNBC with high PD-L1 13,78
(Keytruda) antibody expression
Atezolizumab Anti-PD-L1 monoclonal PD-L1 expression Approved for use in combination 79
(Tecentriq) antibody with nab-paclitaxel and in metastatic
PD-L1-positive TNBC
Nivolumab (Opdivo) Anti-PD-1 monoclonal PD-L1 expression, TMB Investigational use in TNBC, associated 80
antibody with high TMB and a subset of patients with
previously treated mTNBC
Durvalumab (Imfinzi) Anti-PD-L1 monoclonal PD-L1 expression Investigational use, in combination with 81,82
antibody chemotherapy and other ICIs
Ipilimumab (Yervoy) Anti-CTLA-4 monoclonal Enhanced T-cell activation Often combined with anti-PD-1/PD-L1 83
antibody therapies, ongoing trials with tremelimumab
Avelumab (Bavencio) Anti-PD-L1 monoclonal PD-L1 expression Investigational use in combination therapies in 84
antibody metastatic, heavily pre-treated breast cancer
CAR-T-cell therapy CAR-T-cell therapy EGFR, HER2, and eradication of Early-phase clinical trials in TNBC 85
other tumor-specific antigens
Abbreviations: CAR-T-cell: Chimeric antigen receptor T-cell; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; EGFR: Epidermal growth factor
receptor; HER2: Human epidermal growth factor receptor 2; ICIs: Immune checkpoint inhibitors; mTNBC: Metastatic triple-negative breast cancer;
PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; TMB: Tumor mutational burden; TNBC: Triple-negative breast
cancer.

Volume 3 Issue 3 (2024) 8 doi: 10.36922/td.3383