Impact of NLRP3 inflammasome activation on prognosis of oral squamous cell carcinoma patients

• Grant number: 21/04040-3
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2022
• End date: April 30, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Gilberto de Castro Junior
• Grantee: Gilberto de Castro Junior
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Evandro Sobroza de Mello ; Fátima Solange Pasini ; Haniel Alves Araujo

Abstract

Chronic inflammation modulates the tumor microenvironment interaction with the immune system and plays a critical role in tumor progression and immune system evasion. NLRP3 inflammasome complex activation is central to the inflammatory response and drives the interleukin-1beta pathway with downstream activation of IL-1beta, IL-6 and IL-18. An important proof of concept of the effects of inflammation modulation in vivo was tested in the CANTOS trial (Ridker et al., NEJM, 2017), evaluating the effect of IL-1beta inhibition in cardiovascular events after acute myocardial infarction. Nevertheless, this cohort of over 10,000 patients showed an unexpected reduction in the incidence and mortality from lung cancer, highlighting the importance of modulating pathways related to inflammasome in the treatment of cancer and motivating the design of new clinical trials. Furthermore, translational studies suggest an important role of inflammasome activation and tumor proliferation in mice and cell lines in head and neck squamous cell carcinoma (SCC). Therefore, we postulate that NLRP3 inflammasome activation and downstream activation of IL-1², IL-18 and IL-6 orchestrates a major role in head and neck squamous cell carcinoma progression and correlates with poorer prognosis. We aim to investigate association ofNLRP3 inflammasome activation biomarkers with prognosis in our cohort including 128 patients with oral cavity SCC (overall and relapse-free survival). Plus, in order to further detail the mechanisms responsible for inflammasome activation and transcriptome correlates in these patients, tumor samples from subjects with higher expression of IL-6 and IL-18 will be submitted to RNA-seq. Therefore, our study will provide sensitive information regarding the mechanisms associated with NLRP3inflammasome activation and its actual clinical impact on survival in patients with oral cavity SCC. Ultimately, this study might provide new insights toward the development of novel biomarkers and therapeutical targets in this setting. (AU)