PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines - 16/04/21
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Abstract |
Triple-negative breast cancer (TNBC) is an invasive tumor with a high incidence of distant metastasis and poor prognosis. In TNBC cells, high PD-L1 expression can induce an immunosuppressive tumor microenvironment, repressing the anti-tumoral immune responses. Although FDA-approved agents targeting the PD-1/PD-L1 axis are potent to eliminate tumoral cells, their immune-related adverse events have become worrisome. As the regulator of gene expression, siRNAs can directly target PD-L1 in breast cancer cells. The gene modification of tumoral PD-L1 can reduce our reliance on the current method of targeting the PD-L1/PD-1 axis. We initiated the study with bioinformatics analysis; the results indicated that TNBC and the MDA-MB-231 cells significantly overexpressed PD-L1 compared to other breast cancer subtypes and cell lines. Our results demonstrated that PD-L1 silencing substantially reduced PD-L1 expression at mRNA and protein levels in MDA-MB-231 cells.
Moreover, our results demonstrated that PD-L1 knockdown reduced cancer cell proliferation and induced apoptosis via intrinsic and extrinsic apoptosis pathways. We observed that PD-L1 silencing effectively inhibited the migration of TNBC cells. Further investigation also displayed that silencing of PD-L1 in breast cancer cells induced T-cell cytotoxic function by upregulating the gene expression of pro-inflammatory cytokines, i.e., IL-2, IFN-γ, and TNF-α, and downregulating the gene expression of anti-inflammatory cytokines, i.e., IL-10, and TGF-β, in a co-culture system.
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Highlights |
• | Triple-negative breast cancer (TNBC) is highly invasive and has a high early recurrence rate. |
• | Silencing of PD-L1 by PD-L1-siRNA in tumor cells induced T-lymphocytes cytotoxic function and inhibited the migration of breast tumor cells. |
• | PD-L1 knockdown can reduce CD25+ Foxp3+ Tregs population in the tumor microenvironment. |
Keywords : Triple-negative breast cancer, PD-L1, SiRNA, Silencing
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Vol 138
Article 111436- juin 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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