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 language | English |
|---|---|
| Pages (from-to) | 283-91 |
| Number of pages | 9 |
| Journal | Cancer Immunology and Immunotherapy |
| Volume | 65 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2016 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells
AU - Palesch, David
AU - Wagner, Johanna
AU - Meid, Annika
AU - Molenda, Nicole
AU - Sienczyk, Marcin
AU - Burkhardt, Jutta
AU - Münch, Jan
AU - Prokop, Lea
AU - Stevanovic, Stefan
AU - Westhoff, Mike-Andrew
AU - Halatsch, Marc-Eric
AU - Wirtz, Christian Rainer
AU - Zimecki, Michal
AU - Burster, Timo
PY - 2016/3
Y1 - 2016/3
N2 - 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.
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.
KW - Brain Neoplasms
KW - Cathepsin G
KW - Cell Line, Tumor
KW - Glioblastoma
KW - Histocompatibility Antigens Class I
KW - Humans
KW - Proteolysis
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1007/s00262-016-1798-5
DO - 10.1007/s00262-016-1798-5
M3 - Article
VL - 65
SP - 283
EP - 291
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
SN - 0340-7004
IS - 3
ER -