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Cystatin F acts as a mediator of immune suppression in glioblastoma

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Abstract

Purpose

Glioblastoma, the most aggressive type of brain cancer, is composed of heterogeneous populations of differentiated cells, cancer stem cells and immune cells. Cystatin F, an endogenous inhibitor of lysosomal cysteine peptidases, regulates the function of cytotoxic immune cells. The aim of this study was to determine which type of cells expresses cystatin F in glioblastoma and to determine the role of cystatin F during disease progression.

Methods

RT-qPCR and immunohistochemistry were used to determine cystatin F mRNA and protein levels in glioblastoma tissue samples. The internalization of cystatin F was analyzed by Western blotting. Enzyme kinetics, real time invasion and calcein release cytotoxicity assays were used to assess the role of internalized cystatin F.

Results

We found that cystatin F was not expressed in non-cancer brain tissues, but that its expression increased with glioma progression. In tumor tissues, extensive staining was observed in cancer stem-like cells and microglia/monocytes, which secrete cystatin F into their microenvironment. In trans activity of cystatin F was confirmed using an in vitro glioblastoma cell model. Internalized cystatin F affected cathepsin L activity in glioblastoma cells and decreased their invasiveness. In addition, we found that cystatin F decreased the susceptibility of glioblastoma cells to the cytotoxic activity of natural killer (NK) cells.

Conclusions

Our data implicate cystatin F as a mediator of immune suppression in glioblastoma. Increased cystatin F mRNA and protein levels in immune, glioblastoma and glioblastoma stem-like cells or trans internalized cystatin F may have an impact on decreased susceptibility of glioblastoma cells to NK cytotoxicity.

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Acknowledgements

We would like to acknowledge Metka Novak, Bernarda Majc and Mateja Mlinar for technical support in processing tissue biopsies, RNA isolation and Fluidigm gene expression analysis and Eva Lasič for critical reading of the manuscript.

Availability of data and materials

The TCGA datasets used in this study can be accessed at: http://gliovis.bioinfo.cnio.es/. The datasets generated during the current study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

List of abbreviations

BSA bovine serum albumin.

C/EBPα CCAAT/enhancer-binding protein-α.

CTL cytotoxic T lymphocyte.

GBM glioblastoma.

GSC glioblastoma stem-like cell.

MpL Macrolepiota procera.

NK natural killer cell.

PBS phosphate buffered saline.

RT room temperature.

TCGA The Cancer Genome Atlas.

Funding

This research was funded by the Slovenian Research Agency, grant numbers P4–0127, J4–1776 to J.K., J3–2516 to M.P.N., P1–0245 to T.L.T., Z3–1870 to B.B. and the European Program of Cross-Border Cooperation for Slovenia-Italy Interreg TRANS-GLIOMA to T.L.T. The funders had no role in the design of the study, in the collection, analyses or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

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Authors and Affiliations

  1. Department of Biotechnology, Jožef Stefan Institute, Jamova cesta 39, SI-1000, Ljubljana, Slovenia

    Emanuela Senjor, Milica Perišić Nanut, Ana Mitrović & Janko Kos

  2. Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000, Ljubljana, Slovenia

    Emanuela Senjor & Janko Kos

  3. Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, SI-1000, Ljubljana, Slovenia

    Barbara Breznik, Ana Rotter & Tamara Lah Turnšek

  4. Institute of Pathology, Medical Faculty, University of Ljubljana, Korytkova 2, SI-1000, Ljubljana, Slovenia

    Jernej Mlakar

  5. Department of Neurosurgery, University Clinical Centre Ljubljana, SI-1000, Ljubljana, Slovenia

    Andrej Porčnik

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  1. Emanuela Senjor
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Contributions

Conceptualization, M.P.N., J.K., E.S.; methodology, M.P.N., B.B., E.S., A.M.; validation, M.P.N.; resources J.M., A.P.; formal analysis, A.R., E.S.; investigation, E.S.; writing and original draft preparation, E.S.; writing - review and editing, M.P.N., B. B, A.M., J.M., A.P., T.L.T, J.K.; visualization, E.S.; supervision, M.P.N., B.B., J.K.; project administration M.P.N., J.K., B.B., T.L.T.; funding acquisition, M.P.N., J.K., B.B., T.L.T. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Janko Kos.

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The study was approved by the National Medical Ethics Committee of the Republic of Slovenia (Approval no. 0120–179 190/2018/4).

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The authors declare that they have no competing interests.

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Senjor, E., Perišić Nanut, M., Breznik, B. et al. Cystatin F acts as a mediator of immune suppression in glioblastoma. Cell Oncol. 44, 1051–1063 (2021). https://doi.org/10.1007/s13402-021-00618-9

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