Our lab is interested in the molecular mechanisms by which granzymes kill tumor and virus-infected cells and how these target cells are able to escape from granzyme-induced killing and thus the immune system. Identification of granzyme inhibitors in certain tumor types or viruses will lead to novel therapeutic strategies to circumvent these inhibitors. Knowledge of how granzymes induce tumor cell death will provide direct novel targets for pro-apoptotic anti-cancer/viral therapies.
Granule-exocytosis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells constitutes the main pathway for eliminating tumor cells and virus-infected cells from our body. In humans, cytotoxic granules contain perforin and five serine proteases called granzymes (GrA, GrB, GrH, GrK, and GrM) that induce cell death by cleaving specific intracellular substrates. Apart from GrA and GrB, however, little is known about the cell death mechanism of GrH, GrK, and GrM. In our lab, we are currently investigating these cell death pathways.
Granzymes activate multiple distinct pathways of cell death with distinct morphological hallmarks that cooperate during cytotoxic lymphocyte cytotoxicity. This redundancy likely evolved to provide protection against tumor cells with diverse strategies to evade immune surveillance. Some tumors can escape from GrB-mediated apoptosis by cytoplasmic expression of the GrB-inhibitor serine protease inhibitor (SERPIN)B9. In analogy, several viruses encode inhibitors against the anti-viral activity of GrB. Unlike GrB, however, inhibitors against the other human granzymes remain unknown. This issue currently is another focus in our lab.
Contact information
Dr. N. Bovenschen
Department of Pathology
Phone: 088-7553889
Email:
n.bovenschen@umcutrecht.nl