Triple-negative breast cancer (TNBC) is the most violent class of tumor and accounts for 20-24% of total breast carcinoma, in which frequently rare mutation occurs in high frequency. The poor prognosis, recurrence, and metastasis in the brain, heart, liver and lungs decline the lifespan of patients by about 21 months, emphasizing the need for advanced treatment. Recently, the adaptive immunity mechanism of archaea and bacteria, called clustered regularly interspaced short palindromic repeats (CRISPR) combined with nanotechnology, has been utilized as a potent gene manipulating tool with an extensive clinical application in cancer genomics due to its easeful usage and cost-effectiveness. However, CRISPR/Cas are arguably the efficient technology that can be made efficient via organic material-assisted approaches. Despite the efficacy of the CRISPR/Cas@nano complex, problems regarding successful delivery, biodegradability, and toxicity remain to render its medical implications. Therefore, this review is different in focus from past reviews by (i) detailing all possible genetic mechanisms of TNBC occurrence; (ii) available treatments and gene therapies for TNBC; (iii) overview of the delivery system and utilization of CRISPR-nano complex in TNBC, and (iv) recent advances and related toxicity of CRISPR-nano complex towards clinical trials for TNBC. 

https://doi.org/10.1016/j.mtbio.2022.100450

Nanomaterial-assisted CRISPR gene-engineering – A hallmark for triple-negative breast cancer therapeutics advancement

Background/Aim: There is a strong association between malignancy and histone deacetylases (HDACs). Histone deacetylase inhibitors (HDACIs) are now being tested as antitumor agents in various clinical trials. We aimed to assess the clinical importance of HDAC-2 in breast cancer (BC). Materials and Methods: A total of 118 BC specimens were examined immunohistochemically. A statistical analysis was conducted in order to examine the relation between HDAC-2 and the clinicopathological features and survival of the patients. Results: Higher HDAC-2 expression was related to lobular histological type of cancer, grade III, and stage III BC. In addition, the disease-free period and overall survival were curtailed and negatively related to the over-expression of HDAC-2. Other factors correlating with worse survival were histological types other than ductal or lobular, and the stage of the disease. Conclusions: This study showed a relationship between HDAC-2 and BC. Further studies are required in order to eventually potentiate the role of HDACIs as anticancer agents in BC.

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Clinical Significance of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer

Histone deacetylase 2 regulates STAT1-dependent upregulation of atypical chemokine receptor 3 to induce M2 macrophage migration and immune escape in hepatocellular carcinoma.

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis have achieved marked and durable efficacy in patients with different solid tumors and have improved their survival. However, the presence of primary or acquired resistance to immune checkpoint blockades results in only a small fraction of patients benefiting from the treatment. An increasing number of preclinical studies have reported that PD-L1 expression in tumor cells is involved in a number of epigenetic changes, including histone modifications, non-coding RNA regulation and DNA methylation. In addition, multiple epigenetic targeting drugs have been demonstrated to directly or indirectly interfere with PD-L1 expression in various cancer models. This provides opportunities to better characterize the regulatory mechanisms of PD-L1 expression and explore novel therapeutic strategies to improve immunosuppressant response rates and overcome drug resistance. The present review focuses on the latest findings and evidence on the epigenetic mechanism regulating PD-L1 expression and discusses the biological and clinical implications of this regulatory mechanism in solid tumors. A rational combination of epigenetic regulation and PD-1/PD-L1 axis blockade may improve the prognosis of patients with solid tumors.

/pdf/epigenetic-modifications-critical-participants-of-the-pd-l1-3t2c7msg.pdf

Epigenetic modifications: Critical participants of the PD-L1 regulatory mechanism in solid tumors (Review)

Gold-Promoting-Satellite to Boost Photothermal Conversion Efficiency of Cu2-Se for Triple Negative Breast Cancer Targeting Therapy

The PD-L1 overexpression is an important event of immune escape and metastasis in triple-negative breast cancer (TNBC), but the molecular mechanism remains to be determined. Interferon gamma (IFNγ) represents a major driving force behind PD-L1 expression in tumor microenvironment, and histone deacetylase 2 (HDAC2) is required for IFN signaling. Here, we investigated the regulation of HDAC2 on the IFNγ-induced PD-L1 expression in TNBC cells. We found the HDAC2 and PD-L1 expression in TNBC was significantly higher than that in non-TNBC, and HDAC2 was positively correlated with PD-L1 expression. HDAC2 promoted PD-L1 induction by upregulating the phosphorylation of JAK1, JAK2, and STAT1, as well as the translocation of STAT1 to the nucleus and the recruitment of STAT1 to the PD-L1 promoter. Meanwhile, HDAC2 was recruited to the PD-L1 promoter by STAT1, and HDAC2 knockout compromised IFNγ-induced upregulation of H3K27, H3K9 acetylation, and the BRD4 recruitment in PD-L1 promoter. In addition, significant inhibition of proliferation, colony formation, migration, and cell cycle of TNBC cells were observed following knockout of HDAC2 in vitro. Furthermore, HDAC2 knockout reduced IFNγ-induced PD-L1 expression, lymphocyte infiltration, and retarded tumor growth and metastasis in the breast cancer mouse models. This study may provide evidence that HDAC2 promotes IFNγ-induced PD-L1 expression, suggesting a way for enhanced antitumor immunity when targeting the HDAC2 in TNBC.

/pdf/histone-deacetylase-2-knockout-suppresses-immune-escape-of-406l92e4wx.pdf

Pengfei Xu

Papers

Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression.