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Epithelial-to-Mesenchymal Transition and its Association with PD-L1 and CD8 T cells in Thyroid Cancer

M. Aghajani,T. Yang,U. Schmitz,A. James,C. McCafferty,P. Souza,N. Niles,Tara Roberts

Published 2020 in Unknown venue

ABSTRACT

Background: Programmed cell death-ligand 1 (PD-L1) has recently been shown to play a role in the regulation of epithelial-to-mesenchymal transition (EMT) in some cancers. However, the relationship between PD-L1 expression, EMT and the inflammatory tumour microenvironment has yet to be investigated in thyroid cancer. Methods: To address this issue, we examined the expression of CD8, PD-L1 and the EMT markers E-cadherin and vimentin in a cohort of papillary thyroid cancer (PTC) patients and investigated the association of these with clinicopathologic characteristics and disease-free survival (DFS). CD8 T cells, PD-L1 and EMT status was assessed in 74 patients with PTC via immunohistochemistry (IHC). The relationship between PD-L1 and EMT was further investigated in three thyroid cancer cell lines (8505C, K1 and FTC-133) via western blot and live cell imaging In order to expand our in vitro findings, the normalised gene expression profiles of 516 thyroid cancer patients were retrieved from The Cancer Genome Atlas (TCGA). An EMT score of each thyroid cancer sample was calculated and correlated with PD-L1 gene expression, or the mean expression of IFN signature genes. Results: PD-L1 positivity was significantly higher in PTC patients exhibiting a mesenchymal phenotype ( p = 0.012). Kaplan-Meier analysis revealed that PD-L1 ( p = 0.045), CD8 ( p = 0.038) and EMT status ( p = 0.038) were all significant predictors for DFS. Sub-analysis confirmed that the poorest DFS was evident in PD-L1 positive patients with EMT features and negative CD8 expression ( p < 0.0001). IFN-γ treatment induced upregulation of PD-L1 and significantly promoted an EMT phenotype in two thyroid cancer cell lines. Conclusions: Our findings suggest that PD-L1 signalling may play a role in stimulating EMT in thyroid cancer. EMT, CD8 and PD-L1 expression may serve as valuable predictive biomarkers in patients with PTC. The combination of EMT inhibitors with immunotherapies targeting the PD-1/PD-L1 axis may be beneficial in cancer patients with mesenchymal metastatic thyroid cancers.

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