Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells

David Palesch, Johanna Wagner, Annika Meid, Nicole Molenda, Marcin Sienczyk, Jutta Burkhardt, Jan Münch, Lea Prokop, Stefan Stevanovic, Mike-Andrew Westhoff, Marc-Eric Halatsch, Christian Rainer Wirtz, Michal Zimecki, Timo Burster

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

To mount an adaptive immune response, MHC I molecules present antigenic peptides to CTLs. Transcriptional reduction of MHC I molecules is a strategy of immune evasion, which impairs the detection of infected or tumorous cells by CTLs. Natural killer (NK) cells, on the other hand, eliminate target cells specifically in the absence of MHC I. Consequently, infected or tumorous cells partly retain their MHC I at the cell surface to avoid NK recognition. However, it remains unclear which protease degrades MHC I molecules and how these cells maintain a limited set of MHC I at the cell surface. Here, we demonstrate that cathepsin G (CatG), a serine protease, found in the endocytic compartment of APCs and, to a lesser extent, CatD and CatS proteolytically degrade MHC I molecules. Inhibition of CatG boosted MHC I expression at the cell surface of primary human immune cells. In contrast, human glioblastoma cells do not harbor active CatG and might have lost the ability to proteolytically degrade MHC I during tumorigenesis to avoid NK-mediated killing. Overexpression of CatG in glioblastoma cells resulted in a rapid and efficient MHC I degradation. In conclusion, CatG is an essential protease for regulating MHC I molecules and thus modulation of CatG activity might present a new avenue for therapeutic intervention.

Original languageEnglish
Pages (from-to)283-91
Number of pages9
JournalCancer Immunology and Immunotherapy
Volume65
Issue number3
DOIs
Publication statusPublished - Mar 2016
Externally publishedYes

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Cathepsin G
Glioblastoma
Peptide Hydrolases
Immune Evasion
Serine Proteases
Adaptive Immunity
Natural Killer Cells
Carcinogenesis
Cats

Keywords

  • Brain Neoplasms
  • Cathepsin G
  • Cell Line, Tumor
  • Glioblastoma
  • Histocompatibility Antigens Class I
  • Humans
  • Proteolysis
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells. / Palesch, David; Wagner, Johanna; Meid, Annika; Molenda, Nicole; Sienczyk, Marcin; Burkhardt, Jutta; Münch, Jan; Prokop, Lea; Stevanovic, Stefan; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Wirtz, Christian Rainer; Zimecki, Michal; Burster, Timo.

In: Cancer Immunology and Immunotherapy, Vol. 65, No. 3, 03.2016, p. 283-91.

Research output: Contribution to journalArticle

Palesch, D, Wagner, J, Meid, A, Molenda, N, Sienczyk, M, Burkhardt, J, Münch, J, Prokop, L, Stevanovic, S, Westhoff, M-A, Halatsch, M-E, Wirtz, CR, Zimecki, M & Burster, T 2016, 'Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells', Cancer Immunology and Immunotherapy, vol. 65, no. 3, pp. 283-91. https://doi.org/10.1007/s00262-016-1798-5
Palesch, David ; Wagner, Johanna ; Meid, Annika ; Molenda, Nicole ; Sienczyk, Marcin ; Burkhardt, Jutta ; Münch, Jan ; Prokop, Lea ; Stevanovic, Stefan ; Westhoff, Mike-Andrew ; Halatsch, Marc-Eric ; Wirtz, Christian Rainer ; Zimecki, Michal ; Burster, Timo. / Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells. In: Cancer Immunology and Immunotherapy. 2016 ; Vol. 65, No. 3. pp. 283-91.
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AB - To mount an adaptive immune response, MHC I molecules present antigenic peptides to CTLs. Transcriptional reduction of MHC I molecules is a strategy of immune evasion, which impairs the detection of infected or tumorous cells by CTLs. Natural killer (NK) cells, on the other hand, eliminate target cells specifically in the absence of MHC I. Consequently, infected or tumorous cells partly retain their MHC I at the cell surface to avoid NK recognition. However, it remains unclear which protease degrades MHC I molecules and how these cells maintain a limited set of MHC I at the cell surface. Here, we demonstrate that cathepsin G (CatG), a serine protease, found in the endocytic compartment of APCs and, to a lesser extent, CatD and CatS proteolytically degrade MHC I molecules. Inhibition of CatG boosted MHC I expression at the cell surface of primary human immune cells. In contrast, human glioblastoma cells do not harbor active CatG and might have lost the ability to proteolytically degrade MHC I during tumorigenesis to avoid NK-mediated killing. Overexpression of CatG in glioblastoma cells resulted in a rapid and efficient MHC I degradation. In conclusion, CatG is an essential protease for regulating MHC I molecules and thus modulation of CatG activity might present a new avenue for therapeutic intervention.

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