5 results on '"Wurzer, Hannah"'
Search Results
2. 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.
- Author
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Wurzer H, Filali L, Hoffmann C, Krecke M, Biolato AM, Mastio J, De Wilde S, François JH, Largeot A, Berchem G, Paggetti J, Moussay E, and Thomas C
- 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
- 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., 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., (Copyright © 2021 Wurzer, Filali, Hoffmann, Krecke, Biolato, Mastio, De Wilde, François, Largeot, Berchem, Paggetti, Moussay and Thomas.)
- Published
- 2021
- Full Text
- View/download PDF
3. Escape of tumor cells from the NK cell cytotoxic activity.
- Author
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Cantoni C, Wurzer H, Thomas C, and Vitale M
- Subjects
- Animals, Humans, Killer Cells, Natural pathology, Neoplasms pathology, Cytotoxicity, Immunologic, Killer Cells, Natural immunology, Neoplasms immunology, Tumor Escape, Tumor Microenvironment immunology
- Abstract
In recent years, NK cells, initially identified as potent cytotoxic effector cells, have revealed an unexpected complexity, both at phenotypic and functional levels. The discovery of different NK cell subsets, characterized by distinct gene expression and phenotypes, was combined with the characterization of the diverse functions NK cells can exert, not only as circulating cells, but also as cells localized or recruited in lymphoid organs and in multiple tissues. Besides the elimination of tumor and virus-infected cells, these functions include the production of cytokines and chemokines, the regulation of innate and adaptive immune cells, the influence on tissue homeostasis. In addition, NK cells display a remarkable functional plasticity, being able to adapt to the environment and to develop a kind of memory. Nevertheless, the powerful cytotoxic activity of NK cells remains one of their most relevant properties, particularly in the antitumor response. In this review, the process of tumor cell recognition and killing mediated by NK cells, starting from the generation of cytolytic granules and recognition of target cell, to the establishment of the NK cell immunological synapse, the release of cytotoxic molecules, and consequent tumor cell death is described. Next, the review focuses on the heterogeneous mechanisms, either intrinsic to tumors or induced by the tumor microenvironment, by which cancer cells can escape the NK cell-mediated attack., (©2020 Society for Leukocyte Biology.)
- Published
- 2020
- Full Text
- View/download PDF
4. Actin Cytoskeleton Straddling the Immunological Synapse between Cytotoxic Lymphocytes and Cancer Cells.
- Author
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Wurzer H, Hoffmann C, Al Absi A, and Thomas C
- Subjects
- Animals, Cell Line, Humans, Immune Evasion, Killer Cells, Natural cytology, Mice, T-Lymphocytes, Cytotoxic cytology, Actin Cytoskeleton metabolism, Actin Cytoskeleton physiology, Immunological Synapses immunology, Killer Cells, Natural immunology, Neoplasms immunology, T-Lymphocytes, Cytotoxic immunology, Tumor Microenvironment immunology
- Abstract
The immune system is a fundamental part of the tumor microenvironment. In particular, cytotoxic lymphocytes, such as cytolytic T cells and natural killer cells, control tumor growth and disease progression by interacting and eliminating tumor cells. The actin cytoskeleton of cytotoxic lymphocytes engaged in an immunological synapse has received considerable research attention. It has been recognized as a central mediator of the formation and maturation of the immunological synapse, and its signaling and cytolytic activities. In comparison, fewer studies have explored the organization and function of actin filaments on the target cancer cell side of the immunological synapse. However, there is growing evidence that the actin cytoskeleton of cancer cells also undergoes extensive remodeling upon cytotoxic lymphocyte attack, and that such remodeling can alter physical and functional interactions at the immunological synapse. In this article, we review the current knowledge of actin organization and functions at both sides of the immunological synapse between cytotoxic lymphocytes and cancer cells, with particular focus on synapse formation, signaling and cytolytic activity, and immune evasion.
- Published
- 2019
- Full Text
- View/download PDF
5. Actin Cytoskeleton Remodeling Drives Breast Cancer Cell Escape from Natural Killer-Mediated Cytotoxicity.
- Author
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Al Absi A, Wurzer H, Guerin C, Hoffmann C, Moreau F, Mao X, Brown-Clay J, Petrolli R, Casellas CP, Dieterle M, Thiery JP, Chouaib S, Berchem G, Janji B, and Thomas C
- Subjects
- Apoptosis, Breast Neoplasms pathology, Cell Line, Tumor, Cytotoxicity, Immunologic, Drug Resistance, Neoplasm, Female, Flow Cytometry, Humans, Leukocytes, Mononuclear cytology, MCF-7 Cells, Peptide Hydrolases metabolism, Signal Transduction, Wiskott-Aldrich Syndrome Protein, Neuronal metabolism, cdc42 GTP-Binding Protein metabolism, Actin Cytoskeleton metabolism, Breast Neoplasms metabolism, Granzymes metabolism, Killer Cells, Natural metabolism
- Abstract
Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here, we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic natural killer (NK) cells. A significant fraction of breast cancer cells responded to NK-cell attack via a surprisingly rapid and massive accumulation of F-actin near the immunologic synapse, a process we termed "actin response." Live-cell imaging provided direct evidence that the actin response is associated with tumor cell resistance to NK-cell-mediated cell death. High-throughput imaging flow cytometry analyses showed that breast cancer cell lines highly resistant to NK cells were significantly enriched in actin response-competent cells as compared with susceptible cell lines. The actin response was not associated with a defect in NK-cell activation but correlated with reduced intracellular levels of the cytotoxic protease granzyme B and a lower rate of apoptosis in target cells. Inhibition of the actin response by knocking down CDC42 or N-WASP led to a significant increase in granzyme B levels in target cells and was sufficient to convert resistant breast cancer cell lines into a highly susceptible phenotype. The actin response and its protective effects were fully recapitulated using donor-derived primary NK cells as effector cells. Together, these findings establish the pivotal role of actin remodeling in breast cancer cell resistance to NK-cell-mediated killing. Significance: These findings establish the pivotal role of the actin cytoskeleton in driving breast cancer cell resistance to natural killer cells, a subset of cytotoxic lymphocytes with important roles in innate antitumor immunity. Cancer Res; 78(19); 5631-43. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
- Full Text
- View/download PDF
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