4.7 Article

PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines

Journal

BIOMEDICINE & PHARMACOTHERAPY
Volume 138, Issue -, Pages -

Publisher

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2021.111436

Keywords

Triple-negative breast cancer; PD-L1; SiRNA; Silencing

Funding

  1. Student Research Committee, Tabriz University of Medical Sciences [61880]
  2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran [59932]

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TNBC with high PD-L1 expression can induce an immunosuppressive tumor microenvironment, but targeting PD-L1 through siRNA can reduce its expression, decrease cancer cell proliferation, induce apoptosis, and effectively inhibit cell migration.
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 PDL1 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-?, and TNF-?, and downregulating the gene expression of anti-inflammatory cytokines, i.e., IL-10, and TGF-?, in a co-culture system.

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