Biologically, this pattern is consistent with an immune-excluded phenotype, in which PD-L1 expression is upregulated independently of T-cell infiltration, often due to stromal barriers or to the transforming growth factor-beta (TGF-β) pathway, a major cellular signaling system that plays a dual role in cancer —acting as both a tumor suppressor in early stages and a tumor promoter in advanced disease. This evidence concerns the gene TGFB1 and cancer.