ArticleFrontiers in immunology2021
Intrinsic Resistance of Chronic Lymphocytic Leukemia Cells to NK Cell-Mediated Lysis Can Be Overcome
Article in Frontiers in immunology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- LIM and SH3 protein 1 deficiency confers resistance to cytotoxic lymphocyte-mediated lysis and immunotherapy in gastric cancer by disrupting cytoskeleton dynamics.Journal for immunotherapy of cancer · 2026Article
- Implications of Rho GTPase signaling in cancer immunotherapy.Biochemical Society transactions · 2026Review
- Statistical Inference of Phenotype-Specific Molecular Mechanisms from Cell Line-Specific Gene Regulatory Networks with Application to Quizartinib Sensitivity.International journal of molecular sciences · 2026Article
- Notch2, a Key Player in Chronic Lymphocytic Leukemia: Mechanism, Microenvironment Interactions, and Therapeutic Implications.Cancers · 2026Review
- RHOA at the intersection of inflammation-driven and sporadic colorectal cancer.Frontiers in immunology · 2026Review
- Cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A New Antibody-Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia.Biomolecules · 2025Article
- Is the tumor cell side of the immunological synapse a polarized secretory domain?Frontiers in immunology · 2024Article
- Pathways and molecules for overcoming immunotolerance in metastatic gastrointestinal tumors.Frontiers in immunology · 2024Review
- Measuring CTL Lytic Granule Secretion and Target Cell Membrane Repair by Fluorescent Lipophilic Dye Uptake at the Lytic Synapse.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Actin cytoskeleton remodeling at the cancer cell side of the immunological synapse: good, bad, or both?Frontiers in immunology · 2023Review
- Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential.Cancers · 2022Review
- The relation of blood cell division control protein 42 level with disease risk, comorbidity, tumor features/markers, and prognosis in colorectal cancer patients.Journal of clinical laboratory analysis · 2022Article
- Dysregulation of circulating CDC42 and its correlation with demographic characteristics, comorbidities, tumor features, chemotherapeutic regimen and survival profile in non-small-cell lung cancer patients.Journal of clinical laboratory analysis · 2022Article
- Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity.Frontiers in immunology · 2022Review
- How natural killer cells avoid self-destruction when killing their targets.PLoS biology · 2021Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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