PD-L1 expression is upregulated via oncogenic activation of the PI3K/Akt/mTOR pathway and is associated with reduced disease-free survival in non-medullary thyroid cancer

  • Background/Purpose: Activation of the PI3K/Akt/mTOR pathway has been shown to upregulate PD-L1 expression and promote resistance to immune checkpoint inhibitors across multiple cancer types. However, in thyroid cancer, the relationship between oncogenic drivers and PD-L1 expression has yet to be examined. We therefore aimed to investigate PD-L1 and its association with the PI3K/Akt/mTOR pathway in thyroid cancer. Methods: Tissue microarrays (TMAs) consisting of 74 papillary thyroid cancer (PTC) cases were constructed and stained for PD-L1 and phospho-Akt (p-Akt (Ser473)). Stained cells were manually counted and analysed for clinicopathological correlations and disease-free survival (DFS). Three thyroid cancer cell lines (8505C, K1 and FTC-133) were treated with inhibitors of PI3K(ly294002), Akt (mk2206) and mTOR (MLN0128), and changes in PD-L1 expression were observed via western blot. Results: PD-L1 and p-Akt (Ser473) were overexpressed in 45.5% and 47.0% of PTC cases, respectively. PD-L1 expression remained the only significant predictor of DFS on multivariate analysis (p=0.031). Patients co-expressing PD-L1 and p-Akt (Ser473) had significantly poorer DFS than patients with single positive or both negative expression (p=0.008). In vitro, inhibition of the PI3K/Akt/mTOR pathway significantly downregulated PD-L1 expression in all cell lines examined. Discussion & Conclusion: Our results suggest that oncogenic activation of the PI3K/Akt/mTOR pathway regulates PD-L1 protein expression in thyroid cancer. The combination of PD-1/L1 antibodies and PI3K/Akt/mTOR inhibitors may serve as an efficacious treatment option in patients with advanced thyroid cancer.

 

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