Cell-intrinsic, non-immunogenic, regulation of PD-L1 in head neck squamous cell carcinoma and its implication on radiosensitivity

• Applicants: Professor Dr. Richard Bauer; Professor Dr. Tobias Ettl, since 7/2022
• Subject Area: Dentistry, Oral Surgery
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438285093

Despite radical surgery and adjuvant (chemo)irradiation, 5-year overall survival of head neck cancer patients is not more than 50-60%. A breakthrough was discovery of the checkpoint inhibitors (e.g. anti CTLA-4 oder anti PD-1) for targeted therapy. For anti PD-1 the efficacy has also been shown for loco-regional advanced or metastasized squamous cell carcinoma of the head and neck, however response rates count not more than 20%. There is increasing evidence for synergistic immunogenic effects between immunotherapy and radiotherapy, thereby enhancing the effectiveness of both therapies. It remains unclear if there also exist cellular interactions, independent from the immune system. Current literature shows that PD-L1 has an intracellular domain which mediates signaling for proliferation, migration and metastasis as well as for therapy resistance of cancer cells. First data of our group confirms this intrinsic signaling of PD-L1 in HNSCC. As PD-L1 activates specific signaling pathways like PI3K/AKT or ERK 1/2 which have been shown to mediate radioresistance it seems reasonable that intrinsic PD-L1 also modulates radiosensitivity. Our pre-data shows different degrees of radiosensitivity of head neck squamous cell carcinoma cell lines. In these cell lines expression of specific signaling pathways (e.g. PI3K/AKT) as well as compartment specific expression of PD-L1 have emerged to be associated with radioresistance. In contrast cancer tissue of HNSCC patients prior to definite (chemo)irradiation displays membrane expression of PD-L1 associated with radiosensitivity. We would like to investigate the cell-intrinsic function of PD-L1 in head neck cancer, its localization, its partners of interaction, and if the resulting signaling influences the efficacy of anti-PD-L1 therapy or radiotherapy. By use of an immunodeficient mouse model with subcutaneously injected HNSCCs, effectiveness of direct intrinsic PD-L1 blockade but also blockade of interacting proteins (anti-PI3K, anti CDK4/6) should be confirmed with regard to overall survival, metastasis and efficacy of irradiation.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Anja Kathrin Wege
• Ehemaliger Antragsteller: Dr. Matthias Hautmann, until 7/2022