基因沉默
三阴性乳腺癌
癌症研究
基因敲除
小干扰RNA
乳腺癌
免疫系统
细胞毒性T细胞
癌细胞
PD-L1
转移
癌症
细胞凋亡
医学
生物
免疫学
细胞培养
免疫疗法
内科学
转染
基因
体外
生物化学
遗传学
作者
Parisa Lotfinejad,Tohid Kazemi,Sahar Safaei,Mohammad Amini,Elmira Roshani Asl,Elham Baghbani,Siamak Sandoghchian Shotorbani,Farhad Jadidi Niaragh,Afshin Derakhshani,Behzad Baradaran,Nicola Silvestris,Behzad Baradaran
标识
DOI:10.1016/j.biopha.2021.111436
摘要
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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