Coumaric acid derivatives as adjuvants in iNKT-based immunotherapy

• Grant number: 23/15339-5
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2024
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandre de Castro Keller
• Grantee: Alexandre de Castro Keller
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Ana Flavia Popi ; João Paulo dos Santos Fernandes ; Nilmar Silvio Moretti

Abstract

The specificity of invariant Natural Killer T (iNKT) cells for lipid antigens expressed on the CD1d molecule and their antitumoral activity in response to its exogenous agonist, ±-galactosylceramide (±GC), make them an alternative for managing cancers resistant to conventional therapies. However, despite the positive results observed in clinical trials, the antitumor efficiency of ±GC remains limited. In this sense, we aim to determine the potential of coumaric acid (p-CA) derivatives as a tool to overcome tumor resistance to ±GC treatment.Tumor resistance to ±GC treatment may be due to the downregulation of CD1d expression, which prevents the direct toxicity of iNKT cells. Additionally, the downregulation of Fas expression contributes to tumor escape from ±GC-mediated antitumoral effect since the induction of apoptosis by the FasL/Fas pathways is one of the principal cytotoxic mechanisms triggered by ±GC/CD1d-induced iNKT activation.Recently, we demonstrated that p-CA esterification improves its cytostatic and cytotoxic capacities over murine and human melanomas. Further experiments revealed that butyl-coumarate (b-pCA) induces CD1d and Fas expression in the murine melanoma cells B16-F10, indicating this compound as an alternative to potentiate the ±GC antitumoral activity. Although the mechanisms involved in these phenomena are still unclear, a preliminary analysis with qPCR indicated that the b-pCA acts as a histone deacetylase inhibitor (iHDAC). In this sense, we intend to corroborate the inhibitory effect of b-pCA on HDACs, explore other chemical derivatives of p-CA, and use experimental models to evaluate the effects of these compounds on tumor resistance to ±GC immunotherapy.Therefore, this project aims to introduce new approaches into the field of research developed in the laboratory, contribute to strengthening collaborations and enhancing the scientific skills of new students, and modernize the methodologies used by our team. (AU)