Cystatin F acts as a mediator of immune suppression in glioblastoma

Senjor, Emanuela; Nanut, Milica Perišić; Breznik, Barbara; Mitrović, Ana; Mlakar, Jernej; Rotter, Ana; Porčnik, Andrej; Turnšek, Tamara Lah; Kos, Janko

doi:10.1007/s13402-021-00618-9

Cited by 11 publications

(12 citation statements)

References 59 publications

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“…Therefore, these cells can survive treatment and give rise to recurrences [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. In addition, stem cells interact with the TME, and their interplay is mandatory to develop biological resistance and sustain the tumorigenic process [ 31 , 39 ]. General features of GSCs are treatment resistance and association with tumor recurrence.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor-associated microglia and macrophages accumulate in perivascular and perinecrotic hypoxic niches, where they start a crosstalk with the staminal compartment ultimately promoting disease progression and relapse after treatments [ 17 , 37 , 39 , 40 , 41 , 73 ]. Mechanisms of crosstalk have only been investigated in a few seminal studies [ 29 , 32 , 33 , 34 , 35 , 36 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

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Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through a ‘Seed-and Soil’ Approach: A Systematic Review

et al. 2022

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Ever since the discovery of tumor-associated immune cells, there has been growing interest in the understanding of the mechanisms underlying the crosstalk between these cells and tumor cells. A “seed and soil” approach has been recently introduced to describe the glioblastoma (GBM) landscape: tumor microenvironments act as fertile “soil” and interact with the “seed” (glial and stem cells compartment). In the following article, we provide a systematic review of the current evidence pertaining to the characterization of glioma-associated macrophages and microglia (GAMs) and microglia and macrophage cells in the glioma tumor microenvironment (TME). Methods: An online literature search was launched on PubMed Medline and Scopus using the following research string: “((Glioma associated macrophages OR GAM OR Microglia) AND (glioblastoma tumor microenvironment OR TME))”. The last search for articles pertinent to the topic was conducted in February 2022. Results: The search of the literature yielded a total of 349 results. A total of 235 studies were found to be relevant to our research question and were assessed for eligibility. Upon a full-text review, 58 articles were included in the review. The reviewed papers were further divided into three categories based on their focus: (1) Microglia maintenance of immunological homeostasis and protection against autoimmunity; (2) Microglia crosstalk with dedifferentiated and stem-like glioblastoma cells; (3) Microglia migratory behavior and its activation pattern. Conclusions: Aggressive growth, inevitable recurrence, and scarce response to immunotherapies are driving the necessity to focus on the GBM TME from a different perspective to possibly disentangle its role as a fertile ‘soil’ for tumor progression and identify within it feasible therapeutic targets. Against this background, our systematic review confirmed microglia to play a paramount role in promoting GBM progression and relapse after treatments. The correct and extensive understanding of microglia–glioma crosstalk could help in understanding the physiopathology of this complex disease, possibly opening scenarios for improvement of treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through a ‘Seed-and Soil’ Approach: A Systematic Review

et al. 2022

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“…In colorectal tumors, high CysF mRNA levels were shown to correlate with an increased risk of liver metastasis and poor survival [ 209 , 210 ]. Furthermore, CysF gene expression was shown to be higher in glioblastoma tissues than in normal brain tissues, and CysF mRNA levels were shown to correlate with shorter patient survival [ 211 , 212 ]. Finally, CysF was found to be expressed in patient‐derived glioblastoma stem‐like cells [ 211 ].…”

Section: Lysosomal Peptidases In Cancer Progressionmentioning

confidence: 99%

“…Furthermore, CysF gene expression was shown to be higher in glioblastoma tissues than in normal brain tissues, and CysF mRNA levels were shown to correlate with shorter patient survival [ 211 , 212 ]. Finally, CysF was found to be expressed in patient‐derived glioblastoma stem‐like cells [ 211 ]. Recently, it was shown that extracellular CysF attenuates granzyme‐mediated cytotoxicity in CTLs [ 213 ] and decreases the susceptibility of a glioblastoma cell line to NK cytotoxicity [ 211 ].…”

Section: Lysosomal Peptidases In Cancer Progressionmentioning

confidence: 99%

“…Finally, CysF was found to be expressed in patient‐derived glioblastoma stem‐like cells [ 211 ]. Recently, it was shown that extracellular CysF attenuates granzyme‐mediated cytotoxicity in CTLs [ 213 ] and decreases the susceptibility of a glioblastoma cell line to NK cytotoxicity [ 211 ]. Apart from the effects on properforin and granzyme activation, increased extracellular CysF levels can affect the activity of immune cells through several additional mechanisms.…”

Section: Lysosomal Peptidases In Cancer Progressionmentioning

confidence: 99%

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Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

et al. 2022

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Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.

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Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells

Senjor,

Pirro,

Švajger

et al. 2023

Cell. Mol. Life Sci.

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Cystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients. Graphical abstract

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Cystatin F acts as a mediator of immune suppression in glioblastoma

Cited by 11 publications

References 59 publications

Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through a ‘Seed-and Soil’ Approach: A Systematic Review

Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through a ‘Seed-and Soil’ Approach: A Systematic Review

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells

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