Intrinsic Resistance of Chronic Lymphocytic Leukemia Cells to NK Cell-Mediated Lysis Can Be Overcome
Actin Cytoskeleton
/ drug effects
Biomarkers
Cell Line, Tumor
Cytotoxicity, Immunologic
/ drug effects
Fluorescent Antibody Technique
HLA-G Antigens
/ immunology
Humans
Immunological Synapses
/ immunology
Immunophenotyping
Killer Cells, Natural
/ drug effects
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Tumor Microenvironment
/ genetics
cdc42 GTP-Binding Protein
/ antagonists & inhibitors
B cell neoplasms
Cdc42
actin cytoskeleton
immune evasion
immunological synapse
natural killer (NK)
tumor immunology
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
19
10
2020
accepted:
23
04
2021
entrez:
10
6
2021
pubmed:
11
6
2021
medline:
29
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34108958
doi: 10.3389/fimmu.2021.619069
pmc: PMC8181408
doi:
Substances chimiques
Biomarkers
0
HLA-G Antigens
0
CDC42 protein, human
EC 3.6.5.2
cdc42 GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
619069Informations de copyright
Copyright © 2021 Wurzer, Filali, Hoffmann, Krecke, Biolato, Mastio, De Wilde, François, Largeot, Berchem, Paggetti, Moussay and Thomas.
Déclaration de conflit d'intérêts
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.
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