PD-L1 In Breast Cancer Research Articles

Regulation of PD-L1 in breast cancer.

e23088 Background: Programmed death ligand 1 (PD-L1, CD274) is currently being investigated as a therapeutic target in breast cancer (BC), however its transcriptional regulation has not been elucidated. Methods: Three BC cells lines, one negative (MCF7) and two positive (MDA-MB-231, BT549) for PD-L1 were used. Protein expression of potential regulators of PD-L1, including Myc, STAT3, p-rpS6 (mTOR effector), Erk and p53 was assessed by western blotting and immunohistochemistry. Furthermore, transfections with small interfering RNAs (siRNAs) of selected proteins or plasmids and pharmacologic inhibition were performed. Fluorescent in situ hybridization (FISH) analysis was used for PD-L1 gene amplification studies. Publically available gene expression data derived from The Cancer Genome Atlas (TCGA) database (cBioportal) were analyzed for correlations between mRNA levels of PD-L1 and potential regulators. Results: PD-L1 gene amplification was not detected in BC cells expressing PD-L1, suggesting non-genetic regulation of PD-L1 expression. Additionally, the correlation between CD274 transcript levels and copy-number alterations (CNA) in primary BC was weak. Pharmacological treatment with either Myc (expressed in MDA-MB-231) or mTOR (p-rpS6 expressed in all three cell lines) inhibitors did not affect PD-L1 expression. STAT3 protein was expressed in all cell lines and STAT3 mRNA levels had a weak positive correlation with PD-L1 (Spearman’s rho = 0.25) in the TCGA dataset. Both gene silencing using STAT3 siRNA and pharmacologic inhibition of STAT3 activity resulted in decreased PD-L1 protein levels in BT549 and MDA-MB-231 cells respectively. Multiple DNA binding sites for STAT3 were identified in silico on the PD-L1 gene promoter suggesting that the observed regulatory effects are likely transcriptional. Conclusions: STAT3 can act as an inducer of PD-L1 expression, while Myc and mTOR seem to have no effect in PD-L1 regulation in BC.

Prognostic Value of PD-L1 in Breast Cancer: A Meta-Analysis.

Programmed cell death 1 ligand 1 (PD-L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD-L1 and breast cancer survival remains unclear. Here, we present the first meta-analysis to investigate the prognostic value of PD-L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD-L1 expression and breast cancer survival. Fixed- and random-effect meta-analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD-L1 overexpression was found in 25.8% of breast cancer patients. PD-L1 (+) associated with several high-risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2-rich and Basal-like p = 0.000). PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640-1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). PD-L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD-L1 assessment assay and well-controlled clinical trials are warranted to clarify its prognostic and therapeutic value.

Targeting the host immune system: PD-1 and PD-L1 antibodies and breast cancer

This article describes the role of the PD-1 axis and reviews current data and future directions inhibiting PD-1 and PD-L1 in breast cancer. Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Higher response rates are seen in triple negative breast cancer, compared with hormone receptor positive disease. Variability in requirements for tumor PD-L1 expression, and variations in testing complicate cross trial comparisons. A fifth phase Ib trial reported a 38% response rate in metastatic triple negative breast cancer treated with the combination of a PD-L1 inhibitor and nab-paclitaxel chemotherapy. Treatment is generally well tolerated, with low rates of immune toxicity including hypothyroidism, pneumonitis, hepatitis, colitis, and hypophysitis, occurring even months after the end of therapy. Immune checkpoint inhibitor therapy has recently been shown to have clinical efficacy in the treatment of breast cancer. The most compelling data are in the triple negative subtype, with responses documented in hormone receptor positive disease as well. Numerous trials are evaluating various combination strategies and biomarkers in early and late stage disease to enhance immunogenicity and response.

29P - XIST overrides the regulatory effect of miR-194 on its immunomodulatory target PD-L1 in breast cancer

29P - XIST overrides the regulatory effect of miR-194 on its immunomodulatory target PD-L1 in breast cancer