Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface

Friedman, Daniel L.; Simmonds, Poppy; Hale, Alexander; Bere, Leoma; Hodson, Nigel; White, Mike; Davis, Daniel M.

doi:10.1242/jcs.258570

Cited by 34 publications

(31 citation statements)

References 82 publications

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“…Lytic granule secretion from CTLs was observed at the base of these protrusions so that it was spatially localised to the areas of force exertion on the target cell membrane ( 89 ). It is interesting to note that the stiffness of a target cell can also modulate NK cell and CTL activation itself, with activation significantly reduced against target cells exhibiting a soft phenotype or grown on a soft substrate ( 90 , 91 ). Thus, alterations in cell stiffness at the whole-cell level, such as during malignancy, or at the nanoscale, at the immune synapse, may potently manipulate the sensitivity of cancerous or infected cells to perforin.…”

Section: Mechanisms Of Resistance To Cytotoxicitymentioning

confidence: 99%

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

2022

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Cytotoxic lymphocytes are critical in our immune defence against cancer and infection. Cytotoxic T lymphocytes and Natural Killer cells can directly lyse malignant or infected cells in at least two ways: granule-mediated cytotoxicity, involving perforin and granzyme B, or death receptor-mediated cytotoxicity, involving the death receptor ligands, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). In either case, a multi-step pathway is triggered to facilitate lysis, relying on active pro-death processes and signalling within the target cell. Because of this reliance on an active response from the target cell, each mechanism of cell-mediated killing can be manipulated by malignant and infected cells to evade cytolytic death. Here, we review the mechanisms of cell-mediated cytotoxicity and examine how cells may evade these cytolytic processes. This includes resistance to perforin through degradation or reduced pore formation, resistance to granzyme B through inhibition or autophagy, and resistance to death receptors through inhibition of downstream signalling or changes in protein expression. We also consider the importance of tumour necrosis factor (TNF)-induced cytotoxicity and resistance mechanisms against this pathway. Altogether, it is clear that target cells are not passive bystanders to cell-mediated cytotoxicity and resistance mechanisms can significantly constrain immune cell-mediated killing. Understanding these processes of immune evasion may lead to novel ideas for medical intervention.

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Section: Mechanisms Of Resistance To Cytotoxicitymentioning

confidence: 99%

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

2022

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“…It is therefore likely that significantly stiffer late stage iRBCs are more easily phagocytosed during infection. Likewise, CD8+ T cells and natural killer cells show greater activation ( Liu et al., 2021 ), form larger synapses ( Friedman et al., 2021 ), and demonstrate greater cytotoxicity against stiffer targets ( Tello-Lafoz et al., 2021 ). Critically, cytotoxic T cells and macrophages accumulate in the cerebral vasculature during cerebral malaria, and are thought to be at least partially responsible for disease severity ( Riggle et al., 2020 ).…”

Section: Section 2 Infected Red Blood Cell Mechanics and Cytoadhesionmentioning

confidence: 99%

Biophysical Tools and Concepts Enable Understanding of Asexual Blood Stage Malaria

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et al. 2022

Front. Cell. Infect. Microbiol.

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Forces and mechanical properties of cells and tissues set constraints on biological functions, and are key determinants of human physiology. Changes in cell mechanics may arise from disease, or directly contribute to pathogenesis. Malaria gives many striking examples. Plasmodium parasites, the causative agents of malaria, are single-celled organisms that cannot survive outside their hosts; thus, thost-pathogen interactions are fundamental for parasite’s biological success and to the host response to infection. These interactions are often combinations of biochemical and mechanical factors, but most research focuses on the molecular side. However, Plasmodium infection of human red blood cells leads to changes in their mechanical properties, which has a crucial impact on disease pathogenesis because of the interaction of infected red blood cells with other human tissues through various adhesion mechanisms, which can be probed and modelled with biophysical techniques. Recently, natural polymorphisms affecting red blood cell biomechanics have also been shown to protect human populations, highlighting the potential of understanding biomechanical factors to inform future vaccines and drug development. Here we review biophysical techniques that have revealed new aspects of Plasmodium falciparum invasion of red blood cells and cytoadhesion of infected cells to the host vasculature. These mechanisms occur differently across Plasmodium species and are linked to malaria pathogenesis. We highlight promising techniques from the fields of bioengineering, immunomechanics, and soft matter physics that could be beneficial for studying malaria. Some approaches might also be applied to other phases of the malaria lifecycle and to apicomplexan infections with complex host-pathogen interactions.

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“…Cell softness also prevented immune synapse formation and target-induced apoptosis of natural killer cells, in addition to cytotoxic T cells. Human NK cells more effectively secreted granzymes A and B, FasL, granulysin, and IFNγ on stiffer substrates than softer substrates ( 112 ), a trend that was similarly observed in the cytotoxic T cells. Moreover, a study in cervical and colorectal cancer cell lines revealed NMII paralog-specific activity and localization induced MHCI and CD59 uptake via clathrin-mediated endocytosis ( 113 ).…”

Section: Implications For Disease Severity and Clinical Outcomementioning

confidence: 65%

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.

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Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface

Cited by 34 publications

References 82 publications

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

Biophysical Tools and Concepts Enable Understanding of Asexual Blood Stage Malaria

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

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