Page 11 - TD-3-3

Tumor Discovery Immune and epigenetic therapies for TNBC

Table 1. Inhibitors targeting myeloid‑derived suppressor cells in triple‑negative breast cancer
Inhibitor Mechanism of action Clinical data available Notes References
ATRA Induces differentiation ATRA+DAPT (γ-secretase inhibitor) Demonstrated reduction in MDSCs 40,41
of MDSCs into mature together sensitize the cell lines with and enhanced immune response
myeloid cells NOTCH1 ICD, which blocks the internal in TNBC
aberration and constituent expression of
NOTCH1, thus making the TNBC cells
render sensitivity to ATRA
Pexidartinib CSF1R inhibitor, reduces Demonstrate that the PTX and PLX3397 Reduces MDSCs and 42
(PLX3397) MDSC accumulation combination provides consistent therapeutic tumor-associated macrophages in
improvement across several TNBC models TNBC
Entinostat HDAC inhibitor, reduces Phase II trial in TNBC NCT02708680 Terminated early due to low accrual 43
MDSC function and NCT01234532
proliferation Primary endpoint not met
NCT01349959
PI3Kγ inhibitors Inhibits PI3Kγ signaling Phase II trials in TNBC (Mario-3) These effects allowed for decreasing 44
(e.g., IPI-549) in MDSCs, reducing NCT03961698 immune suppression and
their immunosuppressive increasing immune activation,
activity leading to the activation and
proliferation of T-cells that can
attack cancer cells
Abbreviations: ATRA: All-trans retinoic acid; CSF1R: Colony-stimulating factor 1 receptor; HDAC: Histone deacetylase; IMCs: Immature myeloid
cells; MDSCs: Myeloid-derived suppressor cells; NOTCH1 ICD: NOTCH1 intracellular domain; PI3Kγ: Phosphoinositide 3-kinase gamma; PTX:
Paclitaxel; TNBC: Triple-negative breast cancer.

Table 2. Inhibitors targeting regulatory T‑cells in triple‑negative breast cancer
Inhibitor name Mechanism of action Target pathway Clinical trials References
CTLA-4 monoclonal CTLA-4 blockade CTLA-4 NCT01928394 49,50
antibody (Ipilimumab) NCT02536794
PD-L1 inhibitor PD-1 blockade PD-1 KEYNOTE-522 51,52
(Pembrolizumab and NCT02425891
Atezolizumab)
Anti-CD25 antibody Depletes Tregs inhibiting antitumor immunity IL-2 receptor (CD25) NCT01521676 53
TGF-β inhibitor Blocks TGF-β signaling preventing the TGF-β pathway Clinical trials still recruiting 54,55
(Galunisertib) development of drug-resistant cancer stem cells MSB0011359C
DNMT inhibitor Epigenetic modification, increasing the DNA methylation - 56
(Decitabine) antitumor T-cell response
HDAC inhibitor Epigenetic modification by promoting T-cell Histone deacetylation - 57
infiltration in the tumor
Abbreviations: CTLA-4: Cytotoxic T-lymphocyte associated protein 4; DNA; Deoxyribonucleic acid; DNMT: DNA methyltransferase; HDAC: Histone
deacetylase; IL-2: Interleukin 2; PD-1: Programmed cell death protein 1; TGF-β: Transforming growth factor-beta; Tregs: Regulatory T-cells.

influence the progression of TNBC throughout its course, Immunohistochemistry staining of tumor tissues
from initiation to metastasis, and may also be useful in with TAM markers has shown that individuals with
determining TNBC patients’ DFS and OS. In TNBC, a higher pathological grades frequently have higher TAM
61
high TAM density correlates with a worse prognosis and a levels. In addition, patients with higher TAM infiltration
higher likelihood of tumor metastasis. Recent studies have have significantly shorter OS and disease-free intervals
62
revealed that macrophages are not homogeneous; rather, compared to those with lower TAM infiltration. For
64
they can be classified into numerous subgroups based on TAM identification, CD163 and CD68 markers are most
+
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phenotype, function, and the need for polarization. Based commonly used. Prior research has demonstrated that
64
on chemokines and cytokines receptor expression, the CD163 TAM infiltration, rather than CD68 , is linked
+
+
classification of TAMs is either alternatively activated M2 to a poor prognosis in TNBC patients, as indicated by
subtype or classically activated M1 subtype. 63 multivariate analysis. Because CD204 and CD163
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65
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Volume 3 Issue 3 (2024) 5 doi: 10.36922/td.3383