a Cancer Research Center , Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation , Doha , Qatar.
b College of Medicine and Health Sciences , United Arab Emirates University , Al Ain , United Arab Emirates.
Expert Opin Ther Targets. 2018 Jun;22(6):547-557. doi: 10.1080/14728222.2018.1471137. Epub 2018 May 2.
Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals.
PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays.
We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression.
These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression.
乳腺癌是最常见的癌症，也是全球女性癌症相关死亡的主要原因。三阴性乳腺癌（TNBC）占乳腺癌的 15%，具有明显的转移特征，预后不良。一些肿瘤中观察到强烈的 PD-L1 表达，支持其逃避免疫监视。针对 PD-L1 可能是乳腺癌患者有前途的治疗方法。我们通过抑制上游 STAT1 和 STAT3 信号来研究 PD-L1 组成性表达的潜在分子机制。
使用定量 PCR 和 Western blot 测量三种乳腺癌细胞系中 PD-L1 的表达。使用药理学抑制剂和 siRNA 阻断 STAT1 和 STAT3 的激活。使用 ChIP 和共免疫沉淀测定来研究 PD-L1 组成性表达的机制。
我们发现单独抑制 STAT1 和 STAT3 的激活部分地下调了 PD-L1，而联合抑制则完全下调了 PD-L1 的表达。此外，我们的结果表明，pSTAT1-pSTAT3 在细胞质中二聚化并转移到细胞核，在那里它们与 PD-L1 启动子结合并诱导 PD-L1 表达。
这些发现为联合靶向 STAT1 和 STAT3 开发免疫为基础的癌症疗法提供了依据，以下调 PD-L1 的表达。
