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 (p_E = 0.001; p_S = 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.

Background: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived immune modulation might contribute to the anti-metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. Methods: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0–7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). Results: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. Conclusions: BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.

Maxillofacial hard tissues have several differences compared to bones of other localizations of the human body. These could be due to the different embryological development of the jaw bones compared to the extracranial skeleton. In particular, the immigration of neuroectodermally differentiated cells of the cranial neural crest (CNC) plays an important role. These cells differ from the mesenchymal structures of the extracranial skeleton. In the ontogenesis of the jaw bones, the development via the intermediate stage of the pharyngeal arches is another special developmental feature. The aim of this review was to illustrate how the development of maxillofacial hard tissues occurs via the cranial neural crest and pharyngeal arches, and what significance this could have for relevant pathologies in maxillofacial surgery, dentistry and orthodontic therapy. The pathogenesis of various growth anomalies and certain syndromes will also be discussed.