Influence of the immune system on the induction of ferroptosis in tumor cells

• Grant number: 21/09718-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2021
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Lucas de Abreu Ferreira Machado
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM
• Associated scholarship(s): 23/02861-5 - Unraveling the role of HO-1 in modulating the tumor microenvironment, BE.EP.IC

Abstract

During the last decades, several therapeutic approaches that use the pharmacological induction of cell death by apoptosis have been developed for the treatment of cancer. Despite the efficiency of these therapies, eventually, the tumor cells develop intrinsic resistance to the drugs used in this process. Therefore, finding new ways to induce tumor cell death has great relevance. Given the relationship between excess iron and tumor progression, approaches involving iron metabolism have been explored. Among them, ferroptosis proves to be a promising mechanism in inducing regulated cell death in tumor cells. Recent evidence has shown that inflammatory responses promoted by cells of the immune system contribute to the increase in ferroptosis and the attenuation of tumor progression. This work hypothesizes that cells of the immune system can act by negatively modulating pathways interconnected with the regulation of redox metabolism. In addition, macrophage subtypes could increase iron support in the tumor microenvironment, resulting in the greater formation of reactive oxygen species (ROS). Due to the absence of pathways that act by decreasing the production of ROS, it increases lipid peroxidation and therefore also increases ferroptosis. The objective is to evaluate the influence of iron in conjunction with cell-mediated responses of the immune system on metabolic pathways interconnected with ferroptosis in tumor cells. For this, in silico, in vitro, and in vivo models will be performed in order to assess the response generated both in the tumor cell and in its microenvironment. It is expected to demonstrate that the immune system can be a way of intrinsically favoring pathways associated with ferroptosis in tumor cells. (AU)