Molecular Mechanisms of Synergistic Effects of Radiotherapy, ATR and Distinct Immune-Checkpoint Inhibition to Enhance Immunological Responses in HNSCC

• Applicant: Dr. Tina Jost
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561650663

Tumors in the head and neck region still represent a therapeutic challenge and, in particular, non-HPV-associated tumors have a poorer prognosis due to their reduced radiosensitivity. The use of targeted inhibitors combined with has been promising for a long time. The targeted combination of inhibitors of the DNA damage response with radiotherapy can effectively increase anti-tumor effects. By combining AZD0156 (an ATM inhibitor, ATMi) or VE-822 (an ATR inhibitor, ATRi) with radiotherapy, we were able to show that both inhibitors have a similar toxic effect on the tumor cell, but differ in their immunological consequences. The combination of VE-822 and radiotherapy is also clinically superior. Nevertheless, there is a lack of sufficient data to explain the superior effect of VE-822. In preliminary data, we were able to show that the combination of ATM inhibitor AZD0156 and irradiation inhibits many immune-relevant molecules in the cell, which could explain the superiority of VE-822 in terms of anti-tumor effects. Therefore, we would like to investigate the immunological potential of both inhibitors with regard to their effect in head and neck squamous cell carcinoma. The effect of both combinations on the induction of immunogenic cell death as well as the role of DNA damage recognition and signaling (cGAS-Sting, RIG-I) will be investigated. With the help of established co-culture models, the influence of the (altered) immunophenotype of the tumor cells can also be analyzed directly on immune cells (e.g. CD8+ T cells, natural killer cells). Finally, we want to validate our findings in an immune-competent mouse model as part of this project. Based on the analyzed immunophenotype of the tumor cells treated with combination therapy, we will add a suitable immunotherapy to the existing combination in order to maximize the anti-tumor effects in our HNSCC model. We will also focus on the tumor-infiltrating immune cells, the activation status of immune cells in the spleen, bone marrow and lymph nodes as well as signaling molecules such as chemokines and cytokines in the tumor microenvironment. Our research goals are summarized in the following three objectives: A) Insights into differences in immune changes of HNSCC tumor cells between RT+ATRi compared to RT+ATMi as a basis for improving multimodal therapies. B) Impact of the ATRi-driven immunogenic phenotype of HNSCC tumor cells on the activity and function of CD8+ T cells and NK cells (allogeneic and syngeneic model systems). C) Using the murine SCC VII syngeneic HNSCC mouse model, combined treatments will be performed and the local and systemic immune microenvironment will be analyzed in detail, with a focus on immune cell modulators such as CXCL14.

• DFG Programme: Research Grants
• International Connection: France, Norway
• Co-Investigators: Professorin Dr. Cornelia Brunner; Professorin Dr. Kirsten Lauber
• Cooperation Partners: Professor Dr. Eric Deutsch; Professor Dr. Oliver Tomic