Cathepsin X activity does not affect NK-target cell synapse but is rather distributed to cytotoxic granules

Jakoš, Tanja (author), Prunk, Mateja (author), Pišlar, Anja (author), Kos, Janko (author)

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.

• Language: English
• Keywords: cytotoxic cells, cathepsin X, NK-92, immunological synapse, LFA-1
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 17 str.
• Numbering: Vol. 22, iss. 24, art. 13495
• PID: 20.500.12556/RUL-136937
• UDC: 615.37: 616-097
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms222413495
• COBISS.SI-ID: 89846019
• Publication date in RUL: 25.05.2022

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 16.12.2021

Secondary language

• Language: Slovenian
• Keywords: citotoksične celice, katepsin X, imunološka sinapsa, imunogenost, imunoterapija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P4-0127
• Name: Farmacevtska biotehnologija: znanost za zdravje

• Funder: ARRS - Slovenian Research Agency
• Project number: J4-1776
• Name: Izboljšanje imunoterapevtske vrednosti NK celic z modulacijo cistatina F