摘要
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-beta 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-beta induced TGFBI expression, and knockdown of TGFBI increased the growth of lung ADC cells. Given that TGF-beta 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.