Inverse Regulation of TLR4 and PD-L1 Shapes the Inflammatory Tumor Microenvironment in Oral Squamous Cell Carcinomas

Abstract

Background: The interactions between malignant cells and immune cells within the tumor microenvironment (TME) significantly influence cancer development and progression. This study aimed to analyze and correlate the expression of TLR4 and PD-L1 with the immune response, clinical characteristics, and prognosis of oral squamous cell carcinomas (OSCC).

Methods: Our retrospective multicentric study consisted of the assessment of 166 OSCC specimens for TLR4, PD-L1, CD8, and Ki-67 expression in a TMA-based immunohistochemistry analysis.

Results: Our findings indicated an inverse correlation between the expression of PD-L1 and TLR4 (r = -0.348, p = 0.014, and r = -0.269, p = 0.049, superficial tumor site and in overall analysis, respectively). On the other hand, PD-L1 expression in the deep and superficial invasive front positively correlated with CD8+ T tumor infiltrating lymphocytes (TIL) in a statistically significant manner. A logistic regression analysis was performed to assess the impact of each variable on the clinical outcome with at least 5-year follow-up after the initial OSCC diagnosis. The multivariate model revealed that advanced T stage (T3-T4), presence of lymph node metastasis (N+), as well as performing chemotherapy were statistically significantly associated with OSCC mortality.

Conclusion: These findings taken together suggest that there is a differential regulation of the immune response coordinated by activation of PD-L1 or TLR4 affecting T cell response.

Keywords: CD8; PD‐L1; TLR4; mortality; oral squamous cell carcinoma; tumor infiltrating lymphocytes (TIL); tumor microenvironment.