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Targeting cystatin F activation enhances NK cell cytotoxicity in glioblastoma models
Emanuela Senjor1,2, Anamarija Habič3,4, Urban Švajger5
1Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
Introduction:
Glioblastoma (GBM) is a highly invasive brain tumor with limited treatment options and poor prognosis. Natural killer (NK) cells are key effectors of antitumor immunity, capable of eliminating cancer stem-like cells. However, GBM creates an immunosuppressive microenvironment that limits NK cell function. Here, we identify cystatin F as an immunosuppressive factor involved in regulating NK cell granule-mediated cytotoxicity.
Methods:
We analyzed cystatin F expression in GBM and its correlation with immune exhaustion markers. NK cell activity was compared between GBM patients and healthy donors. In vitro co-cultures of cystatin F-expressing microglial cells and glioblastoma stem-like cells were used to assess NK cell function. To block cystatin F activation from dimeric to active monomeric form, a small-molecule inhibitor of cathepsin V, the activating protease, was applied.
Results:
Cystatin F expression correlated with immune exhaustion and suppression markers in GBM. NK cells from patients showed reduced cytotoxicity compared to healthy donors. Co-cultures confirmed that cystatin F-expressing microglia impaired NK cell cytotoxicity, while inhibition of cathepsin V restored NK cell function in standard cytotoxicity assays, 3D spheroids, and microfluidic perfused models.
Discussion:
These results indicate that cystatin F mediates NK cell suppression in GBM. Targeting its activation enhances NK cell cytotoxicity, offering a potential strategy to improve NK-based immunotherapy for glioblastoma.
Insights
Cystatin F suppresses natural killer (NK) cell function in glioblastoma (GBM). Inhibiting cystatin F activation restores NK cell antitumor activity, offering a new immunotherapy target for GBM.
Area of Science:
- Neuro-oncology
- Immunology
- Molecular Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor outcomes.
- Natural killer (NK) cells combat tumors, but GBM's immunosuppressive environment hinders them.
- Cystatin F is identified as a key factor in this immune suppression.
Purpose of the Study:
- Investigate cystatin F's role in GBM-induced NK cell dysfunction.
- Determine if targeting cystatin F can restore NK cell antitumor activity.
Main Methods:
- Analyzed cystatin F expression and immune markers in GBM.
- Compared NK cell activity in GBM patients versus healthy donors.
- Used in vitro co-cultures and cathepsin V inhibition to assess NK cell function.
Main Results:
- Cystatin F levels correlated with immune exhaustion in GBM.
- GBM patients' NK cells showed reduced cytotoxicity.
- Blocking cathepsin V, which activates cystatin F, restored NK cell function.
Conclusions:
- Cystatin F actively suppresses NK cell activity in the GBM microenvironment.
- Inhibiting cystatin F activation presents a promising strategy for enhancing NK cell-based glioblastoma immunotherapy.
