Abstract
Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.
Highlights
In oral cancer, the programmed cell death ligand 1/programmed cell death receptor 1(PD-L1/PD-1) signaling pathway represents an important immune checkpoint, which limits immune reactions and contributes to the tumor immune-escape [1]
We demonstrated earlier that PD-L1 and PD-1 expression in oral squamous cell carcinoma (OSCC) was significantly higher compared to normal oral mucosa (NOM) [6,7]
In total 99 oral leukoplakia samples, 45 OSCC and 20 NOM were analyzed in the current study
Summary
The programmed cell death ligand 1/programmed cell death receptor 1(PD-L1/PD-1) signaling pathway represents an important immune checkpoint, which limits immune reactions and contributes to the tumor immune-escape [1]. PD-1 inhibitors are used in advanced stage OSCC with a missing curative surgical or radiooncological treatment option. In some of these patients PD-1 blocking leads to long lasting responses [2]. The PD-1 receptor and its ligands PD-L1 and PD-L2 are important modulators of the immune system. Numerous tumor cells overexpress PD-L1 as a strategy to evade immune responses. The expression of PD-L1 on tumor cells may play an important role in suppressing T cell immune activity and may help malignant cells to escape from the immune system [5]. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. The association between overexpression and malignant transformation, dysplasia and inflammation were examined
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