Ionizing Radiation and Extracellular Vesicle Biogenesis in Head and Neck Cancer: Implications for PD-L1 and Tumor Microenvironment Modulation

• Grant number: 25/04298-1
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Wanessa Fernanda Altei
• Grantee: Wanessa Fernanda Altei
• Host Institution: Hospital do Câncer de Barretos. Barretos , SP, Brazil
• City of the host institution: Barretos
• Associated researchers: Alexandre Arthur Jacinto ; Heloisa Sobreiro Selistre de Araújo ; Lidia Maria Rebolho Batista Arantes ; Renato José da Silva Oliveira

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a significant global health challenge, with high locoregional failure rates and poor treatment responses. Clinical outcomes with the combination of radiotherapy (RT) and immunotherapy remain unsatisfactory, largely due to resistance mechanisms within the tumor microenvironment (TME). One of such mechanisms involves extracellular vesicles (EVs), which play a crucial role in cancer progression, treatment resistance, and immune modulation. This project aims to investigate a novel aspect of treatment resistance in HNSCC by focusing on the role of EVs, particularly exosomes, and the sorting of PD-L1 (a key immune checkpoint molecule) into these EVs after RT in vitro. We hypothesize that ionizing radiation increases exosome biogenesis and the sorting of PD-L1 in a dose-dependent manner, thereby altering the TME and contributing to tumor resistance. No previous research has specifically examined how radiation influences exosome biogenesis or how PD-L1 is sorted into these vesicles, particularly in the context of higher, modern radiation doses. To address this gap, we will employ state-of-the-art equipment and advanced methodologies, including fluorescence-based tools, to study radiation-induced responses in vitro and track the increase in exosome biogenesis. We will also establish co-cultures of tumor cells, immune cells, and EVs to explore the dynamic interactions within the irradiated TME. The ultimate goal is to achieve a better understanding of how EV biogenesis and PD-L1 sorting contribute to treatment resistance in HNSCC. By identifying the role of EVs in this process, this project could propose innovative studies to improve treatment outcomes in HNSCC by modulating the TME. (AU)