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

Abstract

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 p21^CIP1 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 p21^CIP1 expression in lung ADC cells. Moreover, inhibiting FAK via pharmacologic or genetic approaches decreased CITED2 but increased p21^CIP1 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 p21^CIP1, 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.