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Tumor Discovery Immune and epigenetic therapies for TNBC

omics methods to stratify the immune subtypes of TNBC, patients are a favorable prognostic factor since prior studies
distinguishing between “hot” and “cold” phenotypes. have demonstrated that these individuals typically had
A “hot” tumor is characterized by lower clonal heterogeneity, higher disease-free survival (DFS) and OS than patients
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high levels of TILs, macrophages, checkpoint molecules, with low levels of TIL. The influence of TILs on tumor
and type 1 interferon (IFN) signaling. These features make immunosurveillance and immunosuppressive pathways
it sensitive to ICIs and are associated with a good prognosis. may contribute to this phenomenon. Evaluation of the
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Stromal signatures and quiescent immune activity, in clinical connections between the overall TIL count and
addition to a higher mutation burden (including MYC and specific TIL subtype levels in TNBC can enhance the ability
PTEN/PI3K mutations) and neoantigen (B7-H4), are the to forecast treatment outcomes and prognostic trends for
main characteristics of a “cold” tumor. A poor response to this BC subtype, given the distinct clinicopathological and
ICIs is caused by low numbers of TILs and an enrichment immunohistochemical features of TNBC.
of immunosuppressive neutrophils or MDSCs. 18
2.2. MDSCs
Research offers a model to identify possible targets that
can turn “cold” TNBC tumors into “hot” ones, in addition The TME regulates the differentiation and transformation
to helping identify a subset of TNBCs with superior of normal myeloid cells by secreting different soluble
therapeutic outcomes from ICIs. Wang et al. developed factors that convert them into immunosuppressive cells,
a unique technique to enhance the effectiveness of ICI resulting in the establishment of a tumor-promoting
on “cold” tumors by identifying AURKA inhibitors that “macroenvironment” that significantly inhibits the
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might stimulate T-cell infiltration by reprogramming effectiveness of cancer immunotherapy. MDSCs are a
the tumor immunological phenotype of TNBC. Since diverse group of cells with strong immunosuppressive
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lymphocyte infiltration and IFN-γ status characterize the properties, found in the tumor-bearing mice’s spleen and
“T-cell inflamed” phenotype (also known as “hot tumors”), tumor tissues, as well as in cancer patients’ peripheral
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they are essential for the efficacious administration of blood and tumor locations. MDSCs are distinguished
anti-programmed cell death-1 (PD-1)/programmed cell by their diverse makeup and potent immunosuppressive
death ligand 1 (PD-L1) therapy. As opposed to this, “non- abilities, which support immunosuppressive environment
inflamed” or “cold tumors” do not have T-cell infiltration, development through several strategies, such as nutrition
while other myeloid or immune cells may be present. depletion and regulatory Tregs recruitment. 31
Immunotherapy treatment of cold tumors is extremely Myeloid cells responsible for inhibiting the immune
difficult since no developed or sustained adaptive immune system significantly contribute to tumor growth and
response has occurred. 20 spread by helping tumors evade immune surveillance. They
accumulate in tumor and inflammatory tissues, affecting
2.1. TILs B-cells and other cell populations within the inflammatory
TILs are present in the BC microenvironment among response, as well as immune cell function. Furthermore,
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several cell types and are essential for carcinogenesis and Lu et al. have reported that MDSCs play a role in creating
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cancer progression, according to growing evidence. a premetastatic niche, thereby accelerating the spread of
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Interestingly, as compared to HR-positive subtypes, TNBC tumors. Under normal circumstances, immature myeloid
tumors show comparatively higher TIL numbers, making cells rapidly differentiate into three types of immune cells
them the most immunogenic BC subtype. TILs are mainly – macrophages, mature granulocytes, or dendritic cells –
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made up of immune cells that have a significant impact each with distinct roles in the body’s defense mechanisms.
on patient prognosis by either stimulating or inhibiting However, in the presence of inflammation, cancer, and
tumor growth. According to studies, patients with elevated infection, immature myeloid cells become dysfunctional,
TIL levels in metastatic BC frequently have better therapy including becoming MDSCs, when they are unable
outcomes compared to those without. Furthermore, to differentiate appropriately. This dysfunction, such
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higher TIL levels in BC patients are associated with a better as reduced T-cell and L-selectin expression, generally
response to chemotherapy. 24-26 contributes to MDSC-mediated immunosuppression.
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A greater rate of pathologic complete response (pCR) According to Xu et al., while MDSCs primarily impact
was observed in TNBC patients with high TIL levels T-cell tolerance, they have also been reported to suppress a
compared to those with low TIL levels, as reported by Gao variety of other cells.
et al. The study also added that for every 10% rise in the In addition, myeloid stem cells are activated by
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level of TIL, TNBC patients have a higher pCR rate (OR interleukin-34 (IL-34), which, during differentiation into
1.09, 95% CI 1.02 – 1.16). Furthermore, TILs in TNBC monocytic MDSCs (M-MDSCs), recruits Tregs while
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Volume 3 Issue 3 (2024) 3 doi: 10.36922/td.3383