Role of the high mobility group box 1 signalling axes via the receptor for advanced glycation end-products and toll-like receptor-4 in the immunopathology of oral lichen planus

Abstract High mobility group box 1 (HMGB1) is an extremely conserved DNA‐binding protein that stabilizes nucleosomes and facilitates gene transcription in mammalian cells. When released extracellularly, HMGB1 becomes an alarmin that can mediate systemic diseases. High mobility group box 1 signals via two main receptors: receptor for advanced glycation end‐products (RAGE) and toll‐like receptor‐4 (TLR4). We hypothesized that HMGB1 expression is increased in patients with oral lichen planus (OLP) relative to healthy controls. Therefore, HMGB1 and its receptors were mapped in tissue biopsies from 25 patients with OLP and from 20 healthy controls by immunostaining and ImageJ analysis. High mobility group box 1 was induced in oral keratinocytes in all patients with OLP. The band‐like cell infiltrate in patients with OLP revealed very strong staining for RAGE. Likewise, TLR4 was overexpressed throughout OLP mucosa which co‐localized with HMGB1. In conclusion, we suggest that OLP could partly be an HMGB1‐mediated condition by creating a proinflammatory loop cycle via RAGE‐ and TLR4‐signalling axes, which may contribute to the chronicity of this disease

The prognostic value of immune checkpoints in oral squamous cell carcinoma

Abstract Background: Despite the importance of immune checkpoints in immunotherapy, the prognostic value of these molecules remains controversial in oral squamous cell carcinoma (OSCC). We performed a systematic review to investigate the prognostic significance of the immune checkpoints in OSCC. Materials: A systematic search was conducted in Ovid Medline, Scopus and Cochrane libraries, and all studies that evaluated the prognostic significance of immune checkpoints in OSCC were systematically retrieved. Results: Twelve immune checkpoints/modulators were studied for their prognostic values in OSCC patients between 1985 and 2017. Seven immune checkpoints (FKBP51, B7‐H4, B7‐H6, ALHD1, PD‐L1, B7‐H3 and IDO1) were reported to be associated with poor patients’ survival in at least one study, and five (CTLA‐4, TLT‐2, VISTA, PD‐L2 and PD‐1) did not have a significant prognostic value. PD‐L1 results were controversial as it was reported to be associated with both better and worse patients’ survival. Conclusions: Even though immune checkpoint markers had high expectation for OSCC prognostication, our systematic review revealed that the majority of them had been studied only once. The other molecules, which had been studied more than once, had controversial findings, except B7‐H3

Immune checkpoints indoleamine 2,3‐dioxygenase 1 and programmed death‐ligand 1 in oral mucosal dysplasia

Abstract Background: Oral mucosal dysplasia is a histologic feature of potentially malignant disorders that is associated with the risk of transformation to carcinoma. Dysplastic cells use many strategies during their transformation to cancer, including escape from the immune mediated destruction. We hypothesized that adaptive immunity is inhibited by activation of distinct immune checkpoint molecules, such as indoleamine 2,3‐dioxygenase 1 (IDO1) and programmed death‐ligand 1 (PD‐L1). Methods: We collected 63 oral dysplasia samples from 47 patients. Nine biopsies from alveolar mucosa were taken during wisdom teeth extractions were used as healthy controls. Tissue samples were stained and scored for IDO1 and PD‐L1. Additionally, dysplasia grades and inflammatory cell infiltration were evaluated. Eight patients were followed up to 36 months to evaluate dysplasia progression, inflammation, and immune checkpoint molecules expression. Results: Dysplastic epithelium had significantly lower IDO1 expression than that of healthy controls. PD‐L1 positive cells in the lamina propria were mainly in dysplastic samples and seldom in healthy controls. Dysplasia grade was associated negatively with epithelium IDO1 and positively with IDO1 and PD‐L1 expression in the lamina propria. There was a positive association between dysplasia grade and level of inflammatory cell infiltration. During follow‐up, dysplasia grade, inflammatory cell infiltration, and the immune checkpoint expression fluctuated over time. Conclusions: Immune checkpoint molecules IDO1 and PD‐L1 are modulated during oral epithelial dysplastic changes, and their expression is associated with inflammatory cell infiltration in the lamina propria. As immune checkpoint molecules expression fluctuates over time, these molecules are not useful as biomarkers for oral mucosal dysplasia progression