# PLK1/vimentin signaling facilitates immune escape by recruiting Smad2/3 to PD-L1 promoter in metastatic lung adenocarcinoma

## TL;DR

This study shows how vimentin, when phosphorylated by PLK1, helps lung cancer cells spread and avoid the immune system by boosting PD-L1 expression.

## Contribution

The novel finding is that PLK1-mediated phosphorylation of vimentin at S339 activates TGF-β signaling and PD-L1 expression in metastatic lung adenocarcinoma.

## Key findings

- Phosphorylation of vimentin at S339 by PLK1 enhances metastasis and PD-L1 expression in lung adenocarcinoma.
- Phosphomimetic vimentin at S339 interacts with p-Smad2 to promote PD-L1 expression and immune escape.
- High expression of VIM, PLK1, and CD274 correlates with poor survival in lung adenocarcinoma patients.

## Abstract

The prerequisite function of vimentin for the epithelial–mesenchymal transition (EMT) is not clearly elucidated yet. Here, we show that vimentin phosphorylated by PLK1, triggers TGF-β-signaling, which consequently leads to metastasis and PD-L1 expression for immune suppression in lung adenocarcinoma. The clinical correlation between expression of both vimentin and PLK1, and overall survival rates of patients was significant in lung adenocarcinoma but not in squamous cell carcinoma. The phosphorylation of vimentin was accompanied by the activation of PLK1 during TGF-β-induced EMT in lung adenocarcinoma. Among the several phosphorylation sites determined by phospho-proteomic analysis and the site-specific mutagenesis, the phosphorylation at S339 displayed the most effective metastasis and tumourigenesis with the highest expression of PD-L1, compared with that of wild-type and other versions in both 3D cell culture and tail-vein injection metastasis models. Phosphomimetic vimentin at S339 interacted with p-Smad2 for its nuclear localization, leading to the expression of PD-L1. Clinical relevance revealed the inverse correlation between the survival rates of patients and the expressions of VIM, PLK1, and CD274 in primary and metastatic lung adenocarcinoma. Thus, PLK1-mediated phosphorylation of vimentin activates TGF-β signaling pathway, leading to the metastasis and immune escape through the expression of PD-L1, functioning as a shuttling protein in lung adenocarcinoma.