Abstract
BackgroundThe T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified.MethodsWe have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections.ResultsInduction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation.ConclusionsWe have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0421-2) contains supplementary material, which is available to authorized users.
Highlights
The T-cell inhibitory molecule Programmed death ligand-1 (PD-L1) (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients
We have demonstrated that PD-L1 expression is induced upon epithelial to mesenchymal transition (EMT) process and is highly significantly associated with claudin-low, a subtype of breast cancer, known to have EMT features
The correlation between PD-L1 expression and mesenchymal features in breast cancer cell lines prompted us to investigate if such relationship is physiologically relevant to the normal human breast
Summary
The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. Alsuliman et al Molecular Cancer (2015) 14:149 between its expression in cancer cells and patients’ clinicopathological status has been demonstrated (Reviewed in [8]). In many cancer types PD-L1 expression is associated with worse outcome, suggesting the contribution of PD-L1 to promote tumor escape from the immune system [9,10,11,12]. We and other have previously demonstrated that PD-L1 expression is associated with triple negative breast cancer [10, 13,14,15]. PD-L1 and T-reg can provide an immune suppressive microenvironment, leading to tumor escape from immune recognition and promotes tumor growth
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