Establishment and characterization of an orthotopic, lymphogenic-metastasizing and immunocompetent HNSCC mouse model for the investigation of radioimmunological therapy approaches for head and neck tumors

• Applicant: Dr. Sandrina Körner
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548987239

The aim of the proposed project is to develop a mouse model to investigate the role of cervical lymph nodes in the response of head and neck squamous cell carcinoma (HNSCC) to combined immunotherapy with PD-1 antibodies and radiotherapy. In our own preliminary work, we were able to generate murine tumor cell lines by administering 4-NQO in immunocompetent mice, whose mutation profile and similarity to human noxae-induced HNSCC cell lines will now be investigated and described in more detail at the genetic level using whole exome sequencing and RNA-sequencing. In addition, these cell lines will also be further characterized at the functional level using proliferation and migration assays. As the two PD-1 antibodies pembrolizumab and nivolumab are currently the only immune checkpoint inhibitors approved in the EU for the treatment of HNSCC patients, but their indication is still limited to the relapsed/metastatic and therefore palliative treatment situation, numerous clinical studies have focused on the expansion of potential areas of application in recent years. For example, the multicenter, global KEYNOTE-412 trial investigated the combination of platinum-based radiochemotherapy with anti-PD-1 immunotherapy (pembrolizumab) in patients with locally advanced (LA) HNSCC and compared it with platinum-based radiochemotherapy alone. Despite a positive trend, no significant advantage of the experimental therapy over the standard of care of platinum-based radiochemotherapy alone could be demonstrated. Subsequently, possible explanations were sought as to why the addition of anti-PD-1 checkpoint inhibition does not lead to a better therapeutic response to radiochemotherapy. One key theory is that the irradiation of tumor-free cervical lymph node sites ("elective nodal irradiation") suppresses the antitumor immune response, which is supposed to be stimulated by pembrolizumab. However, in order to test this theory in further clinical studies, there is a lack of in vivo data in animal models to support this assumption. In order to investigate this question and generate the data required for clinical trials, an orthotopic, immunocompetent and lymphogenic metastasizing murine HNSCC model is required, which is not available right now and will be established as part of the proposed project. This mouse model represents an ideal methodological basis for further immuno-oncological in vivo studies in the head and neck region and will be used to improve the efficacy of personalized immunotherapy together with simultaneous or sequential radiotherapy in already metastatic HNSCC patients.

• DFG Programme: Research Grants