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Intrinsic Resistance of Chronic Lymphocytic Leukemia Cells to NK Cell-Mediated Lysis Can Be Overcome In Vitro by Pharmacological Inhibition of Cdc42-Induced Actin Cytoskeleton Remodeling.
- Source :
-
Frontiers in immunology [Front Immunol] 2021 May 24; Vol. 12, pp. 619069. Date of Electronic Publication: 2021 May 24 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- Natural killer (NK) cells are innate effector lymphocytes with strong antitumor effects against hematologic malignancies such as chronic lymphocytic leukemia (CLL). However, NK cells fail to control CLL progression on the long term. For effective lysis of their targets, NK cells use a specific cell-cell interface, known as the immunological synapse (IS), whose assembly and effector function critically rely on dynamic cytoskeletal changes in NK cells. Here we explored the role of CLL cell actin cytoskeleton during NK cell attack. We found that CLL cells can undergo fast actin cytoskeleton remodeling which is characterized by a NK cell contact-induced accumulation of actin filaments at the IS. Such polarization of the actin cytoskeleton was strongly associated with resistance against NK cell-mediated cytotoxicity and reduced amounts of the cell-death inducing molecule granzyme B in target CLL cells. Selective pharmacological targeting of the key actin regulator Cdc42 abrogated the capacity of CLL cells to reorganize their actin cytoskeleton during NK cell attack, increased levels of transferred granzyme B and restored CLL cell susceptibility to NK cell cytotoxicity. This resistance mechanism was confirmed in primary CLL cells from patients. In addition, pharmacological inhibition of actin dynamics in combination with blocking antibodies increased conjugation frequency and improved CLL cell elimination by NK cells. Together our results highlight the critical role of CLL cell actin cytoskeleton in driving resistance against NK cell cytotoxicity and provide new potential therapeutic point of intervention to target CLL immune escape.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2021 Wurzer, Filali, Hoffmann, Krecke, Biolato, Mastio, De Wilde, François, Largeot, Berchem, Paggetti, Moussay and Thomas.)
- Subjects :
- Actin Cytoskeleton drug effects
Biomarkers
Cell Line, Tumor
Fluorescent Antibody Technique
HLA-G Antigens immunology
Humans
Immunological Synapses immunology
Immunological Synapses metabolism
Immunophenotyping
Killer Cells, Natural drug effects
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Tumor Microenvironment genetics
Tumor Microenvironment immunology
Actin Cytoskeleton metabolism
Cytotoxicity, Immunologic drug effects
Killer Cells, Natural immunology
Killer Cells, Natural metabolism
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Leukemia, Lymphocytic, Chronic, B-Cell metabolism
cdc42 GTP-Binding Protein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 34108958
- Full Text :
- https://doi.org/10.3389/fimmu.2021.619069