Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma.

Ping‐Chih Hsu,Zhidong Xu,Cheng‐Ta Yang,Yi‐Lin Yang,Jinbai Miao,Joanna You,Chih‐Wei Wang,Zhen Huang,David M Jablons,Yu‐Cheng Wang,Liang You,Wen‐Qian Zhang

doi:10.1111/jcmm.13593

Abstract

Although tumour PD‐L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD‐L1 axis in various cancers, the regulation of PD‐L1 (CD274) expression is unclear. Yes‐associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down‐regulates PD‐L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD‐L1 protein expression compared to H290, MS‐1 and H28 cells. In H2052 and 211H cells, PD‐L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD‐L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD‐L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD‐L1 enhancer region encompassing 2 putative YAP‐TEAD‐binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD‐L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi‐square). We conclude that PD‐L1 is correlated with YAP expression, and inhibition of YAP down‐regulates PD‐L1 expression in human MPM. Further study of how YAP regulates PD‐L1 in MPM is warranted.

Highlights

Malignant pleural mesothelioma (MPM) is a very aggressive cancer that arises from the pleura, and most patients were diagnosed at advanced and unresectable stage.[1]
We found that inhibition of Yes-associated protein (YAP) by Small interfering RNA (siRNA) decreased PD-L1 protein and mRNA expression in H2052 and 211H cells
Chromatin immunoprecipitation (ChIP) assay showed that YAP binds to the PD-L1 enhancer in H2052 cells

Summary

| INTRODUCTION

Malignant pleural mesothelioma (MPM) is a very aggressive cancer that arises from the pleura, and most patients were diagnosed at advanced and unresectable stage.[1]. Because some cancers, including MPM, engage immune checkpoints to escape antitumour immune responses, checkpoint molecule blockade has been pursued as a therapeutic anticancer strategy.[3,4,5] Immunotherapy targeting the immune checkpoint programmed death-1 (PD-1)/PD-ligand (L) 1 axis has been used to treat various. Yes-associated protein (YAP) is a key oncogenic mediator in the Hippo signalling pathway and promotes tumorigenesis, invasion, metastasis and drug resistance in several cancers.[14,15,16,17,18] YAP has been identified in human MPM and is correlated with tumorigenesis and cancer development, suggesting YAP is a therapeutic target for treating advanced unresectable MPM.[19,20,21] YAP regulates tumourassociated immune cells such as myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs).[22,23] YAP may be involved in the immune checkpoint.[22,23] Here, we sought to investigate whether YAP is involved in the regulation of PD-L1 expression of human MPM and whether inhibition of YAP downregulates PD-L1 expression in human MPM

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION