Role of macrophage polarization and PD/PD-L1/2 expression for the progression of leukoplakia to oral squamous cell carcinomas

• Applicant: Professor Dr. Manuel Weber
• Subject Area: Dentistry, Oral Surgery
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 351401691

More than 60% of all oral squamous cell carcinomas (OSCC) derive from oral leukoplakia (OLP). There is no dependable correlation between the histological degree of dysplasia of OLP and the risk of malign transformation. The local immunological response situation (immunity vs. tolerance) could determine the transformation of OLP to invasive carcinomas. While an influence of the immune system on the progression of OSCC is already shown, its contribution on the process of malign transformation is not yet elucidated. The local immunological situation in solid tumors is determined by the polarization (M1 vs. M2) of tumor associated macrophages. In this context, M1 polarized macrophages induce immune response against tumor cells, while M2 macrophages are associated with immune tolerance and tumor progression. In OSCC, the involvement of M2 macrophages on tumor progression and metastatic spread is already shown.Immune tolerance is mediated by inhibitory signaling pathways, so called immune checkpoints. Besides tumor cells, especially macrophages can activate such signaling pathways. The PD/PDL pathway (PD: programmed cell death, PDL: PD Ligand) is one of these immunologic checkpoints, that is involved in the immune escape mechanism of solid tumors like the OSCC.The previous therapy studies with checkpoint inhibitors in solid malignancies showed a clinical success that was not reached by any other second line treatment regime. These encouraging results were achieved in spite of the fact that the physiologic regulation of the immune system by checkpoints is still elusive for the most part. Particularly, data regarding the role of immune checkpoints in the process of malign transformation of precursor lesions are missing.The proposed project aims to answer the question if OLP that transform to invasive cancers in the future already show a state of immune tolerance prior to malign transformation. This immune tolerance might be seen by a shift of macrophage polarization towards M2 and an increased activation of PD/PDL signaling. Using immunohistochemistry and quantitative RT PCR it should be tested, if a collective of 50 OLP that transformed to OSCC during a time interval of 5 years showed a shift towards M2 polarized macrophages and/or an overexpression of the PD1 receptor and the ligands PDL1/PDL2 compared to 50 OLP that showed no malign transformation in the 5 year time window. As control group 50 samples of healthy oral mucosa and 50 OSCC corresponding to the OLP are used.If a shift towards increased M2 polarization of macrophages and/or a PD/PDL overactivation can be shown in the OLPs transforming during the observation period, it would be an evidence of immune tolerance already present in cancer precursor lesions. This could serve as marker predicting the risk of malign transformation of OLP to OSCC and could motivate the use of immune modulatory therapy concepts already in early stages or precursor lesions of OSCC.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Kathrin Brunner; Dr. Maike Büttner-Herold; Dr. Jutta Ries; Privatdozent Falk Wehrhan, Ph.D.