Our goal was to assess the correlation of immune parameters with the response to induction chemotherapy (ICT) in head and neck squamous cell carcinoma (HNSCC) patients. Pretreatment biopsies from 64 patients with HNSCC that received ICT were assessed for PD-L1 protein expression and density of CD8+ and FOXP3+ tumor infiltrating lymphocytes (TIL). In addition, the neutrophil-to-lymphocyte ratio (NLR) was calculated from pretreatment whole blood counts. In total, 55% of cases exhibited PD-L1 combined proportion score (CPS) positivity (≥1% stained cells). PD-L1 CPS positivity correlated with a high density of both CD8+ (p = 0.01) and FOXP3+ (p < 0.001) TILs. There was no correlation between PD-L1 expression or TIL density and NLR values. In univariate analyses, the absence of PD-L1 CPS expression (p = 0.042) and a high NLR (p = 0.034) were significantly correlated with response to ICT. Neither CD8+ TIL (p = 0.99) nor FOXP3+ TIL densities (p = 0.71) were associated with response to ICT. In multivariate analysis, only a high NLR was associated with response to ICT (HR = 4.06, 95% CI = 1.06–15.5, p = 0.04). In addition, a high NLR was also independently associated with lower disease-specific (p = 0.03) and overall survival rates (p = 0.04), particularly in the subset of patients who received definitive surgical treatment. These results suggest that NLR could emerge as a predictive biomarker of response to ICT.

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Activation of WNT/β-catenin signaling has been associated with a non-T-cell-inflamed tumor microenvironment (TME) in several cancers. The aim of this work was to investigate the relationship between β-catenin signaling and TME inflammation in head and neck squamous cell carcinomas (HNSCCs). Membrane and nuclear β-catenin expression, PD-L1 expression, and CD8+ tumor-infiltrating lymphocyte (TIL) density were jointly evaluated by immunohistochemistry in a series of 372 HPV-negative HNSCCs. Membrane β-catenin levels decreased in carcinomas compared to the normal epithelium. Positive nuclear β-catenin was detected in 50 tumors (14.3%) and was significantly associated with a low CD8+ TIL density (168 cells/mm2 versus 293 cells/mm2 in nuclear-β-catenin-negative cases; p = 0.01) and a tendency for a lower expression of PD-L1, resulting in association with a noninflamed TME (i.e., type II, immunological ignorance). Multivariate Cox analysis further demonstrated that low infiltration by CD8+ TILs (HR = 1.6, 95% CI = 1.19–2.14, p = 0.002) and nuclear β-catenin expression (HR = 1.47, 95% CI = 1.01–2.16, p = 0.04) were both independently associated with a poorer disease-specific survival. In conclusion, tumor-intrinsic nuclear β-catenin activation is associated with a non-inflamed TME phenotype and a poorer prognosis, thereby suggesting a possible implication as an immune exclusion mechanism for a subset of HNSCC patients.