Function of Granzyme B in myeloid-derived suppressor cells

Research output: Unpublished contribution to conferencePoster

Abstract

For a long time, only NK cells and cytotoxic T lymphocytes (CTLs) were considered to express granzyme B (GzmB). However, in recent years, several publications reported the expression of GzmB in other cell types as well, for example in mast cells and neutrophils, both in mice and human. A large variety of myeloid-derived suppressor cells (MDSCs)-mediated immune suppressive functions are already described, however there could still remain several unrecognized mechanisms by which MDSCs can counteract the immune system and generate pro-tumoral microenvironment. In our culture system that exists of in vitro-generated MDSCs, we have found a high GzmB expression and an increase in perforin. Perforin together with GzmB is a key component of the lytic machinery of CTLs, leading to activation of caspase-3, which results in apoptosis of the target cell. However evidence of perforin-independent functions of GzmB also exist, such as inflammation and involvement in extracellular matrix degrading by the cleaving of extracellular proteins. Similar observations with regard to GzmB and perforin expression, were made in MDSCs isolated from spleen and tumor from tumor-bearing mice (in breast, lung and colon cancer models). In vitro functional assays did not yet reveal any contributions of GzmB to MDSCs immunosuppressive function, possibly because of the lack of environmental perforin, however GzmB activity assays show functional GzmB expression in MDSCs. There is no evidence yet about the exact mechanisms in which GzmB contributes to the MDSC biology and consequent immune suppression, but we might have discovered a new therapeutic target to dampen MDSC responses and thereby facilitate the introduction of immunotherapy.

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