Impact of plasma-derived exosomes on tumor biogenesis and on the tumor microenvironment in head and neck cancer

• Applicant: Professorin Dr. Marie-Nicole Theodoraki
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 541142520

Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by profound immune suppression which is greatly mediated by exosomes. Exosomes are the smallest extracellular vesicles released by all cells and mediate intercellular communication. HNSCC are avid exosome producers, which are released in the blood but also saliva of patients. These exosomes carry immunosuppressive molecules as PD-L1, tumor antigens or enzymes for production of immunosuppressive adenosine. Further, we showed that HNSCC exosomes` molecular cargo recapitulates the characteristic of the parent tumor cells and represents the immunosuppressive status of the tumor microenvironment (TME), while at the same time it differs significantly from the cargo of healthy donor exosomes. An increasing proportion of HNSCC cases are not caused by smoking but by human papillomavirus (HPV) infection. Studies have shown significant differences in the TME composition and level of immune suppression in the tumor depending on the HPV status, which correlates to overall survival rates. Few studies on chronic lung disease and lung cancer have shown a smoking dependent exosome release with altered RNA and protein cargo with a significant alteration of tumor suppressive miRNAs and tumor associated antigens. Looking at HNSCC, no studies on smoking related exosome alterations are available and HPV associated studies are mainly focused on cell-line derived exosomes. This grant will focus on the effects of plasma- and saliva-derived exosomes on the tumor formation, biogenesis and their impact on the TME. We still don’t know the role of exosomes in tumor biogenesis and if their effects are smoking or HPV related or risk-factor independent. The applicant will investigate the differences in exosomal cargo, functionality, and the ability of tumor biogenesis between healthy non-smokers and healthy smokers and compare the results with exosomes from HNSCC patients (heavy smokers, light smokers/former smokers and non-smokers). Additionally, effects and modulation of the immune system by HPV positive or HPV negative exosomes will be investigated. Next, efforts will be made to evaluate which immune cells are altered by exosomes the most and which signaling pathways are involved using ex vivo explant tumor systems, which represent the whole TME. The following objectives will be addressed: A. Tobacco dependent modulation of plasma- or saliva- derived exosomal cargo and their impact on tumor biogenesis B. Differences of HPV positive and HPV negative exosomes in cancer formation, immune suppression and metastasis C. Exosome-dependent modulation of targeted immune cells within the TME Understanding how exosomes contribute to tumor biogenesis and what role smoking or HPV modulated exosomes play during disease progression may help us to understand the underlying mechanisms with the aim to develop novel treatment strategies and prevention methods.

• DFG Programme: Research Grants
• Major Instrumentation: Nanoparticle Tracking System
• Instrumentation Group: 1950 Partikelzählgeräte und -klassiergeräte (optisch, elektronisch, außer 35