Investigation of lactoferrin-mediated enhancement of cathepsin G activity and immune evasion mechanisms of tumor cells

Collaborative Research Program 2023-2025

Protease-mediated degradation of proteins is critical in a plethora of physiological processes. Neutrophils secret neutrophil serine proteases (NSPs), including cathepsin G (CatG), neutrophil elastase (NE), proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4), together with lactoferrin (LF), as a first cellular immune response against pathogens. We demonstrate that the physiological concentration of LF increases the activity of CatG, with its highest enhancing capacity under acidic conditions, and broadens the substrate selectivity of CatG by an, most likely, induced conformation change in an allosteric manner. Furthermore, LF-mediated enhancement of CatG increases platelet activation. Platelets can coat tumor cells and transfer their major histocompatibility complex I (MHC I) molecules to tumor cells to avoid cytotoxic T lymphocyte (CTL) or natural killer (NK) cell activation, which is essential since tumor cells reduce cell surface MHC I levels to hide tumor-associated antigen and neo-antigen presentation as an immune evasion strategy. This proposal will address the precise interaction between NSPs and LF. Furthermore, we will determine and modulate CatG/LF-mediated MHC I upregulation on platelets by using the CatG inhibitor in order to avoid immune evasion of glioblastoma stem cells. Thus, suggesting a therapeutic use of the CatG inhibitor to prevent the recurrence of glioblastoma caused by migrating glioblastoma stem cells.