Journal Article

Intrinsic PDL1 Signaling Modulates TGFBI‐Mediated Growth Suppression in Lung Adenocarcinoma

Chou, Yu‐Ting, Zheng, Ming‐Yi, Nguyen, Thi Thanh Nha, Chen, Pei‐Yu, Chen, Yuh‐Min, Lin, Ting‐Kuang, Wang, Chun‐Chao

2025

Overview

Programmed death ligand 1 (PDL1) suppresses T‐cell immunity by engaging programmed cell death protein 1 (PD1), and its blockade can activate T‐cell responses. Although PDL1 is a transmembrane protein, its intrinsic signaling role in regulating oncogenesis remains unclear. Our study reveals lung adenocarcinomas (ADCs) exhibit deficient PDL1 expression, which correlates with poor patient prognosis. TGF‐β stimulation induced PDL1 expression, while silencing PDL1 in PDL1‐high lung ADC cells enhanced colony formation, and PDL1 overexpression inhibited lung cancer cell growth. Cell cycle analysis indicated that PDL1 silencing increased S‐phase entry in lung ADC cells. Furthermore, PDL1 expression reduced FAK, ERK, and AKT phosphorylation, increasing cell detachment from the substrate. Gene expression profiling identified TGFBI as a downstream molecule of PDL1. TGF‐β induced TGFBI expression, and knockdown of TGFBI increased the growth of lung ADC cells. Given that TGF‐β regulates CITED2 and p21CIP1 to initiate cell growth arrest, we examined the PDL1‐TGFBI axis's impact on these molecules. Knockdown of PDL1 or TGFBI induced CITED2 expression but decreased p21CIP1 expression in lung ADC cells. Moreover, inhibiting FAK via pharmacologic or genetic approaches decreased CITED2 but increased p21CIP1 expression in PDL1‐silenced lung ADC cells. These findings suggest that intrinsic PDL1‐TGFBI signaling inhibits FAK activation, affecting the CITED2 molecular switch, which induces p21CIP1, ultimately leading to cell growth arrest. Our study provides insights into intrinsic PDL1 signaling in lung ADC oncogenesis and indicates that PDL1 expression could be a biomarker for lung ADC progression. Programmed death ligand 1 (PDL1) is known for suppressing T‐cell immunity, but its intrinsic role in oncogenesis remains unclear. This study demonstrates that PDL1 expression in lung adenocarcinoma (ADC) inhibits tumor cell growth by reducing FAK activation and regulating the CITED2‐p21CIP1 axis, leading to cell growth arrest. These findings reveal PDL1's dual role in immune regulation and tumor suppression, suggesting it as a potential biomarker for lung ADC progression.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - metabolism / Adenocarcinoma of Lung - pathology / AKT protein / Analog to digital converters / Analysis / Apoptosis / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Cell cycle / Cell death / Cell growth / cell growth arrest / Cell Line, Tumor / Cell Proliferation / cellular signaling / Cyclin-dependent kinase inhibitor p21 / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Datasets / Ethylenediaminetetraacetic acid / Extracellular matrix / Flow cytometry / Focal adhesion kinase / Gene expression / Gene Expression Regulation, Neoplastic / Genomes / Growth / Growth factors / Humans / Kinases / Ligands / lung adenocarcinoma / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Medical prognosis / Melanoma / Original / ORIGINAL ARTICLE / PD-1 protein / PDL1 / Phosphorylation / Prognosis / Protein expression / Proteins / Signal Transduction / Squamous cell carcinoma / Survival analysis / T cells / TGF‐β signaling / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism / Transforming growth factor-b / Transforming growth factors / Tumorigenesis / Tumors