Project: Mechanisms of ferroptosis mediated immunoregulation

2022-01-01 – 2025-12-31

Abstract

Ferroptosis is an iron-dependent, necrotic type of cell death driven by lipid peroxidation (LPO) in the plasma membrane. The efficient killing of cancer cells makes ferroptosis a compelling strategy for novel therapy treatments, but the relationship between ferroptosis and the immune system still form a blanc sheet for further research. We found that ferroptotic cells, despite abundant release of damage associated molecular patterns (DAMPs), cytokines and interferons, do not induce an immunological protection against cancer cells, in contrast to necrotic or other known ‘immunogenic’ cell death modalities. We found that dendritic cells exposed to ferroptotic cells fail to support antigen cross presentation, a prerequisite for an adaptive immune response. Oxygen and iron are Earth’s most abundant elements by number of atoms and by mass, respectively, and are at the core of the regulation and execution of ferroptosis. The central hypothesis of the project is that in a world full of oxygen and iron the occurrence of ferroptosis may have resulted in the coevolution of subroutine mechanisms that prevent strong host-mediated responses against the consequences of occasionally, accidently or pathologically occurring ferroptosis. In this project, we aim to identify the tolerance inducing factors (TIFs) and mechanisms how ferroptotic cells instruct dendritic cells (DCs) to tolerance as a way to avoid overreaction by sporadic, infection or trauma induced ferroptosis.