Maximizing Response to Lymphatic-Preserving Immunoradiotherapy through Enhanced Antigen Presentation Strategies in Head and Neck Squamous Cell Carcinoma

• Applicant: Dr. Anais Aurelia Zourelidis
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Hematology, Oncology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551438233

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with an increasing incidence in developed countries and younger populations. Most patients are diagnosed with a locally advanced or distantly metastatic disease, which leads to a poor prognosis. The current standard treatment for advanced head and neck tumors often includes abrogation of lymphatic tissues via surgery or radiotherapy. This involves often large field irradiation, compared to stereotactic body radiation therapy (SBRT), where precisely the gross disease only is treated. Further, for recurrent and/or metastatic forms of HNSCC, the PD1 inhibitors (PD-1i) pembrolizumab or nivolumab are approved. Preliminary work on this project states that a functional lymphatic system is beneficial for the response to immunoradiotherapy (IRT), consisting of radiation and administration of PD1i, as it allows immune trafficking and activation. This work aims to investigate and develop a novel therapeutic approach and thus new strategies to improve the response to IRT in HNSCC. In detail, to enhance tumor antigen presentation after SBRT, we will incorporate TLR9 agonists and anti-CD47 therapy in combination with checkpoint inhibitors in an HNSCC IRT model. Therefore, PD-1i responsive 4MOSC1 and PD-1i resistant 4MOSC2 orthotopic mouse models will be used. The study focuses on the effect of the various components as monotherapy and combinatorial therapy on antigen presentation and the activation of T cells. Moreover, variation of timing and sequencing will be investigated, as the already obtained data demonstrate that sequencing of immunotherapy after stereotactic body radiation therapy (SBRT) results in immunosurveillance coordinated by antigen-presenting cells (APCs) within draining lymphatics. In particular, the effect of a combination of anti-CD-47 or TLR9 agonists and PD1i/IRT on antigen presentation and T cell activation via investigation of APC-T cell interaction, B cell activation, T cell receptor diversity, and antigen-specific T cell activation will be observed. Finally, we will determine whether TLR9 agonists and CD47 blockade can enhance the antitumor response to IRT. Therefore, tumor growth and survival of animals in different arms will be investigated and correlated with the findings of the aforementioned immune measures. Completion of these aims will identify optimized sequencing and novel combinatorial immune therapies in HNSCC. These insights will guide and improve the design of therapeutic strategies that leverage immunologically intact draining lymph nodes in coordinating antitumor immune response and improve outcomes in HNSCC patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Joseph Califano