Rational combination of checkpoint blockade and gene therapy with p14Arf and IFN-b in patient-derived organotypic tumor spheroids

• Grant number: 22/04368-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): September 01, 2022
• Effective date (End): August 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Bryan Eric Strauss
• Grantee: Ana Carolina Martins Domingues
• Supervisor: Russell Williams Jenkins
• 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
• Research place: Massachusetts General Hospital, United States
• Associated to the scholarship: 18/25555-9 - Rational combination between checkpoint blockade and gene therapy with p19Arf and IFN-beta in a mouse model of melanoma, BP.DD

Abstract

The advent of immunotherapy has revolutionized cancer treatment, especially for melanomas, which are tumors with high mutational load and are notably immunogenic. However, immune checkpoint inhibitor therapies are not efficient for a significant share of patients, yet combined strategies have reported additional antitumoral effects. In the research project developed in Brazil, we observed that a combined gene therapy approach with p14Arf and IFN-² induced PD-L1 superexpression in both mouse and human cell lines, thus reducing long-term response to the therapy in melanoma in vivo mouse models. Hence, with the present project, we wish to analyze the modulation of PD-L1 in patient-derived spheroids and the impact of checkpoint blockade on this pathway, as the model allows more adequate analysis of the impact of the therapies in patient cells and its modulations in the tumor microenvironment. (AU)