Targeting inflammatory cell death pathways in squamous cell head and neck carcinomas to improve anti-tumor immunity

• Applicant: Professor Dr. Johannes Brägelmann
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558358560

Head and Neck Squamous Cell Carcinoma (HNSC) impacts 890,000 individuals globally each year. The advent of immunotherapy raised great hopes, however its efficacy in HNSC, even alongside chemotherapy, remains disappointing. Accordingly, patients requiring systemic treatments experience very poor outcomes, highlighting the critical need for better treatments. The tumor microenvironment (TME) plays a pivotal role in immunotherapy success, with 'cold' TMEs showing low immune activity and immunotherapy response, whereas 'hot' TMEs exhibit high immune activity and better responsiveness. As HNSCs frequently contain ‘cold’ TMEs‚ our goal is to transform 'cold' TMEs to 'hot' ones to enhance immunotherapy effectiveness. We aim to achieve this by changing how cancer cells die in response to treatment. Traditional chemotherapy often induces apoptosis, a programmed form of cell death that prevents significant immunological stimulation. However, interfering with the execution of apoptosis has been shown provoke strong immune reactions. In fact, our preliminary data suggests that inhibition of the apoptotic program during chemotherapy can drive HNSC cells into so called caspase-independent cell death (CICD), which is followed by a robust inflammatory response. We propose to leverage this effect by first examining the mechanisms with which caspase-independent cell death enhances HNSC cell immunogenicity and affect immune recognition. Simultaneously, we plan to employ state-of-the-art methodologies such as single-cell RNA sequencing and spatial analysis to dissect the tumor microenvironment and assess the impact of altering cell death mechanisms on its configuration and behavior. Finally, we will test combinatorial treatment strategies including conventional chemotherapy, caspase-independent cell death inducers and immunotherapy using immunocompetent mouse models, patient-derived ex vivo cultures and organoids. We expect that this comprehensive evaluation will identify the most promising therapeutic combinations for converting 'cold' into 'hot' tumor microenvironment. Thereby, we aim to significantly improve the effectiveness of immunotherapies and eventually contribute to improve treatments and outcomes for HNSC patients.

• DFG Programme: Research Grants
• International Connection: Israel
• Co-Investigators: Professor Dr. Jens Peter Klußmann; Professor Dr. Martin Peifer
• International Co-Applicant: Professor Moshe Elkabets, Ph.D.