Proteolytic downregulation of MHC class I molecules to inhibit the immune evasion of glioblastoma

Research output: Chapter in Book/Report/Conference proceedingConference contribution


Glioblastoma multiforme (GBM) is one of the most aggressive tumors. A common reason for treatment failure is the capability of glioblastoma-derived stem cells to infiltrate the surrounding healthy tissue. It was demonstrated that invading/migrating glioblastoma cells downregulate the expression of major histocompatibility complex class I (MHC I), which is a strategy by various cancers and pathogens to evade immune detection by cytotoxic T lymphocytes (CTLs). Natural killer (NK) cells, on the other hand, eliminate target cells in the absence of MHC I. Consequently, glioblastoma cells partly retain their MHC I on the cell surface to avoid recognition by NK cells.
Cell surface MHC I molecules are proteolytic downregulated at the end of their life cycle. However, it remains unclear, which protease degrades MHC I and how glioblastoma cells keep a limited set of MHC I at the cell surface avoiding NK cell activation. We demonstrate that cathepsin G (CatG), a serine protease found in the endocytic compartment of antigen presenting cells (APCs), degrades MHC I molecules. Thus, CatG is an essential protease for post-transcriptional regulation of MHC I molecules. Strikingly, glioblastoma cells do harbor CatG, but not in its active form. We speculate that these cells lost their ability i) to proteolytically degrade MHC I by CatG during tumorigenesis, ii) circumvent complete reduction of cell surface MHC I, and iii) do not activate NK cells. Thus, restoration of CatG activity might present an avenue to therapeutically modulate glioblastoma cells in order to completely remove MHC I from the cell surface and boost the antitumor activity of NK cells.
Original languageEnglish
Title of host publication23rd Polish Peptide Symposium, Spala, Poland. Oral presentation
Publication statusPublished - 2015


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