Cysteine cathepsins L and X differentially modulate interactions between myeloid-derived suppressor cells and tumor cells

Jakoš, Tanja; Pišlar, Anja; Fonović, Urša Pečar; Švajger, Urban; Kos, Janko

doi:10.1007/s00262-020-02592-x

Cited by 13 publications

(6 citation statements)

References 39 publications

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“…The tumor microenvironment is particularly conducive to the development of M2 macrophages and myeloid-derived suppressor cells, which potently suppress the anti-cancer immune response. In comparison to their anti-tumor counterparts, these cells significantly upregulate the expression and activity of cysteine cathepsins (75,239). Blocking these cysteine cathepsins could inhibit their immunosuppressive functions, subsequently alleviating the tumor burden.…”

Section: Cathepsins and Their Inhibitors As Chemotherapeutic Targets For Modulating Immune Cell Functionsmentioning

confidence: 99%

The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

et al. 2021

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Cysteine cathepsins are primarily involved in the degradation and recycling of proteins in endo-lysosomal compartments but are also gaining recognition as pivotal proteolytic contributors to various immune functions. Through their extracellular proteolytic activities within the hematopoietic stem cell niche, they are involved in progenitor cell mobilization and differentiation. Cysteine cathepsins, such as cathepsins L and S contribute to antigen-induced adaptive immunity through major histocompatibility complex class II antigen presentation whereas cathepsin X regulates T-cell migration. By regulating toll-like receptor signaling and cytokine secretion cysteine cathepsins activate innate immune cells and affect their functional differentiation. Cathepsins C and H are expressed in cytotoxic T lymphocytes and natural killer cells and are involved in processing of pro-granzymes into proteolytically active forms. Cytoplasmic activities of cathepsins B and L contribute to the maintenance of homeostasis of the adaptive immune response by regulating cell death of T and B lymphocytes. The expression pattern, localization, and activity of cysteine cathepsins is tightly connected to their function in immune cells. Furthermore, cysteine cathepsins together with their endogenous inhibitors, serve as mediators in the interplay between cancer and immune cells that results in immune cell anergy. The aim of the present article is to review the mechanisms of dysregulation of cysteine cathepsins and their inhibitors in relation to immune dysfunction to address new possibilities for regulation of their function.

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Section: Cathepsins and Their Inhibitors As Chemotherapeutic Targets For Modulating Immune Cell Functionsmentioning

confidence: 99%

The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

et al. 2021

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“…For example, the inhibition of cathepsins influenced the development of osteoclasts from immunosuppressive myeloid-derived suppressor cells, which could contribute to bone metastases [47]. In contrast, the inhibition of cathepsin S was shown to convert regulatory T lymphocytes from immunosuppressive to immunostimulatory cells [48] and inhibition of cathepsin L enhanced cytotoxicity of CD8 + T cells in the co-culture model of tumour cells and myeloid-derived suppressor cells [25]. With this in mind, we investigated whether the inhibition of cathepsin X activity in cytotoxic cells influences LFA-1 affinity modulation, and thus effects formation of stable immunological synapse and cytotoxic activity of cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was shown that cathepsin X influences the reciprocal interactions between tumour cells and tumour promoting myeloid-derived suppressor cells (MDSC). Pharmacological tools for counterbalancing excessive proteolytic activity in tumour tissue might therefore have unexpected consequences for the function of immune cells [25]. Furthermore, the leukocyte specific β2 integrin receptors can be sequentially trimmed at C-terminus by cathepsin X, which modulates their association with adaptor proteins (talin, α-actinin) and fine-tunes their affinity for extracellular ligands [26].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules

Jakoš

Prunk

Pišlar

et al. 2021

IJMS

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Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell–immune cell crosstalk. Selective cathepsin X inhibitors have been proposed as prospective antitumour agents to prevent cancer progression; however, their impact on the antitumour immune response has been overlooked. Previous studies indicate that the migration and adhesion of T cells and dendritic cells are affected by diminished cathepsin X activity. Meanwhile, the influence of cathepsin X inhibition on natural killer (NK) cell function has not yet been explored. Here, we examined the localization patterns of cathepsin X and the role of its inhibitors on the cytotoxicity of cell line NK-92, which is used for adoptive cellular immunotherapy in cancer patients. NK-92 cells depend on lymphocyte function-associated antigen 1 (LFA-1) to form stable immunoconjugates with target cells, providing, in this way, optimal cytotoxicity. Since LFA-1 is a substrate for cathepsin X activity in other types of cells, we hypothesized that cathepsin X could disturb the formation of NK-92 immunoconjugates. Thus, we employed cathepsin X reversible and irreversible inhibitors and evaluated their effects on the NK-92 cell interactions with target cells and on the NK-92 cell cytotoxicity. We show that cathepsin X inhibition does not impair stable conjugate formation or the lytic activity of NK-92 cells. Similarly, the conjugate formation between Jurkat T cells and target cells was not affected by cathepsin X activity. Unlike in previous migration and adhesion studies on T cells, in NK-92 cells cathepsin X was not co-localized with LFA-1 at the plasma membrane but was, rather, redistributed to the cytotoxic granules and secreted during degranulation.

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“…Using Tick Cysteine Protease Inhibitor RHcyst-1, a cathepsin inhibitor and a member of the cystatin 1 family, can decrease and increase the activity of MDSCs in peripheral blood mononuclear cells (PBMC) and the spleen, respectively (102). In breast cancer, cathepsin L/X can also increase the activity of MDSCs in breast cancer and are related to breast cancer invasion (103). Cathepsin B also promotes the formation of neutrophil extracellular traps and modulates tumor aggressiveness in vitro (104).…”

Section: Tumor-associated Immune Cellsmentioning

confidence: 99%

The role of lysosomal peptidases in glioma immune escape: underlying mechanisms and therapeutic strategies

et al. 2023

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Glioblastoma is the most common primary malignant tumor of the central nervous system, which has the characteristics of strong invasion, frequent recurrence, and rapid progression. These characteristics are inseparable from the evasion of glioma cells from immune killing, which makes immune escape a great obstacle to the treatment of glioma, and studies have confirmed that glioma patients with immune escape tend to have poor prognosis. The lysosomal peptidase lysosome family plays an important role in the immune escape process of glioma, which mainly includes aspartic acid cathepsin, serine cathepsin, asparagine endopeptidases, and cysteine cathepsins. Among them, the cysteine cathepsin family plays a prominent role in the immune escape of glioma. Numerous studies have confirmed that glioma immune escape mediated by lysosomal peptidases has something to do with autophagy, cell signaling pathways, immune cells, cytokines, and other mechanisms, especially lysosome organization. The relationship between protease and autophagy is more complicated, and the current research is neither complete nor in-depth. Therefore, this article reviews how lysosomal peptidases mediate the immune escape of glioma through the above mechanisms and explores the possibility of lysosomal peptidases as a target of glioma immunotherapy.

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Cysteine cathepsins L and X differentially modulate interactions between myeloid-derived suppressor cells and tumor cells

Cited by 13 publications

References 39 publications

The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules

The role of lysosomal peptidases in glioma immune escape: underlying mechanisms and therapeutic strategies

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