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Tumor Discovery Immune and epigenetic therapies for TNBC

hindering differentiation into polymorphonuclear MDSCs Tregs have been found to be more common in
(PMN-MDSCs). Although a decline in PMN-MDSCs TNBC, with this higher frequency of Tregs associated
inhibits angiogenesis, the increase in M-MDSCs aids in with higher-grade lesions across all BC subtypes that
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the formation of an immunosuppressive TME, leading to have been investigated. A study by Liu et al. observed
chemotherapy resistance. According to Kajihara et al., an increased proportion of CD4 CD25 Foxp3 Treg
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blocking the differentiation of M-MDSC prevents the infiltration in BC tissues, which was associated with
accumulation of M-MDSC using an ER inhibitor or an decreased OS and progression-free survival, as well as
anti-IL-34 monoclonal antibody, thereby slowing tumor excessive expression of HER2, negative ER and PR status,
growth and restoring chemosensitivity by promoting the and high histology grade. In contrast, Yeong et al.
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accumulation of PMN-MDSC. observed that TNBC patients with a high proportion of
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Recent trials have shown that deactivating MDSCs tumor-infiltrating CD4 CD25 Foxp3 Tregs had a better
can significantly improve immune surveillance against prognosis but also a higher lymph node status and tumor
tumors. TNBC patients have been found to have more grade. However, the accumulation of tumor-infiltrating
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MDSCs than non-TNBC patients. Studies have also Tregs could increase the immunosuppressive capabilities
revealed that the recruitment of MDSCs to metastatic of local cells, thereby subduing anti-tumor immunity
sites and primary tumors is directly facilitated by CXCL2 and promoting tumor growth and invasion. Tregs, CD8/
and CCL22 chemokines through ΔNp63-dependent Treg ratio, and cancer stem cell frequencies have been
activation. The elevated number of MDSCs in basal associated with disease progression, including metastasis
TNBC patients has been linked to high levels of the to the lymph nodes.
transcription factor ΔNp63, which, in turn, promotes Table 2 summarizes various inhibitors targeting Tregs
tumor growth, progression, and metastasis in TNBC that have been studied or have potential relevance for
cells in both human and mouse models. Furthermore, treating TNBC, along with their mechanisms of action and
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MDSCs have been found to release prometastatic factors their clinical development.
such as chitinase 3-like 1 and MMP-9, suggesting their Furthermore, cytotoxic properties of Tregs have been
contribution to the advancement of TNBC in a non- established by previous reviews, which may destroy effector
immunologic manner. Nevertheless, CXCR2/CCR4 T-cells directly, which could account for the correlation
inhibitors have shown promise in lowering angiogenesis, between Foxp3 Tregs infiltration and a low chance of
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metastasis, and MDSC recruitment, indicating a recurrence-free survival in BC patients. 58 Dec rease in T
potential new approach for treating this subgroup of helper 1 cell infiltration and increased tumor infiltration of
TNBC patients. 39 M2 macrophages have been linked with Tregs, along with
The table below (Table 1) presents an overview of elevated TP53 gene mutation rate and alterations of copy
various inhibitors that target MDSCs in TNBC. The table number. Immediately after neoadjuvant chemotherapy,
includes details on the mechanism of action, clinical data, the pCR obtained was associated significantly with Tregs
and significant findings related to each inhibitor. in TNBC in low abundance; this correlation was absent in
Her2-negative/ER-positive subgroups of the disease. On
2.3. Tregs the other hand, in contrast, increased tumor expression
A significant proportion of solid tumors contain Tregs, of several ICI genes was substantially connected with
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which are associated with poor outcomes primarily due to high Treg abundance. Several therapeutic approaches
their role in inhibiting the immune response against tumor that target Tregs suppressive function, including the
progression and fostering immunosuppression. BC is cytotoxic T-lymphocyte-associated protein 4 (CTLA-4),
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one of the several solid tumor types that includes high transforming growth factor beta, and CD39/CD73/Ado
frequencies of T-cells. In TNBC, as well as other subtypes pathways, are presently being developed for use in clinical
of BC and the majority of solid tumors with poorer settings. Nevertheless, the therapeutic advantages of these
prognoses, a high ratio of Forkhead box P3 (FOXP3 ) Treg approaches are probably going to be restricted to situations
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to CD8 T-cells, or high Tregs frequencies among CD4 because Tregs use a variety of pathways to carry out their
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T-cells within TILs, has been linked to worse outcomes. suppressive role. 60
Studies have revealed that increased tumor-infiltrating
Tregs are correlated with reduced DFS, greater tumor 2.4. TAMs
sizes, and higher rates of local recurrence, according to TAMs are leukocytes that infiltrate tumors, originating
the association between Tregs and the clinicopathological from mononuclear cells in the blood, which differentiate
characteristics of TNBC. 45 into macrophages on entering body tissues. TAMs

Volume 3 Issue 3 (2024) 4 doi: 10.36922/td.3383