Clinical relevance and significance of programmed death-ligand 1 expression, tumor-infiltrating lymphocytes, and p16 status in sinonasal squamous cell carcinoma

Abstract

Purpose: Immunotherapy may be a potential alternative for patients with sinonasal squamous cell carcinoma (SNSCC). Data regarding potential immunotherapy targets, such as programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), in SNSCC are limited. In this study, we assessed the prevalence and prognostic value of PD-L1 expression and TILs in p16-negative and p16-positive SNSCC. Patients and methods: Tissues from 96 patients with SNSCC were stained using immunohistochemistry against PD-L1, CD8, and Foxp3 to assess the immune environment. The correlations between PD-L1 expression, TILs, and p16 status were analyzed. Additionally, PD-L1, CD8, and Foxp3 expressions, as well as p16 status, were analyzed in relation to patient clinicopathological variables and prognosis. Results: Twenty-nine (30.2%) patients with SNSCC showed PD-L1 expression in >5% of tumor cells. PD-L1 expression was significantly correlated with poor differentiation and a high level of TILs. PD-L1 expression and the CD8+ and Foxp3+ T-cell infiltrates in p16-negative patients (n=78, 81.2%) and p16-positive patients (n=18, 18.8%) were not significantly different. PD-L1 expression and p16 status were not associated with overall survival (OS) and disease-free survival (DFS). Patients with high CD8+ or Foxp3+ cell infiltration had better clinical outcomes. A multivariate analysis confirmed that CD8 TILs were a significant independent and favorable prognostic factor for OS (p=0.023) and DFS (p=0.008). Conclusion: TILs can play a prognostic role in SNSCC. We did not find differences in immune marker expression between p16-positive and p16-negative SNSCC tissues. The high correlation between PD-L1 expression and TILs indicates that the PD-1/PD-L1 pathway is a promising immunotherapeutic target for SNSCC.

Keywords: biomarker; immunotherapy; prognosis; sinonasal cancer; squamous cell carcinoma.

Figure 1

Representative images of immunohistochemical staining of SNSCC tissue: (A) PD-L1-positive (100×); (B) p16-positive (100×); (C) low CD8 infiltration (400×); (D) high CD8 infiltration (400×); (E) low Foxp3 infiltration (400×); (F) high Foxp3 infiltration (400×). Abbreviations: SNSCC, sinonasal squamous cell carcinoma; PD-L1, programmed death-ligand 1.

Figure 2

Box plots presenting tumor-infiltrating CD8+ and Foxp3+ cells from different groups of SNSCC: (A) CD8+-infiltrating lymphocytes and (B) Foxp3+-infiltrating lymphocytes, according to PD-L1 status; (C) CD8+-infiltrating lymphocytes and (D) Foxp3+-infiltrating lymphocytes, according to p16 status. Abbreviations: SNSCC, sinonasal squamous cell carcinoma; PD-L1, programmed death-ligand 1.

Figure 3

Correlation between Foxp3+-infiltrating lymphocytes and CD8+-infiltrating lymphocytes in SNSCC. Abbreviation: SNSCC, sinonasal squamous cell carcinoma.

Figure 4

Kaplan–Meier curves for (A) OS and (B) DFS in PD-L1-negative and PD-L1-positive patients; Kaplan–Meier curves for (C) OS and (D) DFS in p16-negative and p16-positive patients; Kaplan–Meier curves for (E) OS and (F) DFS in patients stratified for high or low numbers of tumor-infiltrating CD8+ T-cells; Kaplan–Meier curves of (G) OS and (H) DFS for patients stratified for high and low numbers of tumor-infiltrating Foxp3+ T-cells.