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The aim of this study was to investigate the prognostic relevance of β-catenin expression in oral squamous cell carcinoma (OSCC) and to explore relationships with the tumor immune microenvironment. Expression of β-catenin and PD-L1, as well as lymphocyte and macrophage densities, were evaluated by immunohistochemistry in 125 OSCC patient specimens. Membranous β-catenin expression was detected in 102 (81.6%) and nuclear β-catenin in 2 (1.6%) tumors. There was an association between β-catenin expression, tumoral, and stromal CD8+ T-cell infiltration (TIL) and also the type of tumor immune microenvironment (TIME). Tumors harboring nuclear β-catenin were associated with a type II TIME (i.e., immune ignorance defined by a negative PD-L1 expression and low CD8+ TIL density), whereas tumors with membranous β-catenin expression were predominantly type IV (i.e., immune tolerance defined by negative PD-L1 and high CD8+ TIL density). Combined, but not individual, high stromal CD8+ TILs and membranous β-catenin expression was independently associated with better disease-specific survival (HR = 0.48, p = 0.019). Taken together, a combination of high stromal CD8+ T-cell infiltration and membranous β-catenin in the tumor emerges as an independent predictor of better survival in OSCC patients. [ABSTRACT FROM AUTHOR]