Publications
169 results found
Dechantsreiter S, Ambrose AR, Worboys JD, et al., 2022, Heterogeneity in extracellular vesicle secretion by single human macrophages revealed by super-resolution microscopy, JOURNAL OF EXTRACELLULAR VESICLES, Vol: 11
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- Citations: 6
Tuomela K, Ambrose AR, Davis DM, 2022, Escaping death: how cancer cells and infected cells resist cell-mediated cytotoxicity, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
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.
Tuomela K, Mukherjee D, Ambrose AR, et al., 2022, Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 119, ISSN: 0027-8424
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- Citations: 2
Davis DM, 2021, Immune: A Journey into the Mysterious System That Keeps You Alive, SCIENCE, Vol: 374, Pages: 697-697, ISSN: 0036-8075
Diaz-del-Olmo I, Worboys J, Martin-Sanchez F, et al., 2021, Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1 beta Secretion in Human Macrophages, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
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- Citations: 5
Friedman D, Simmonds P, Hale A, et al., 2021, Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface, JOURNAL OF CELL SCIENCE, Vol: 134, ISSN: 0021-9533
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- Citations: 10
Karampatzakis A, Broz P, Rey C, et al., 2021, Antibody afucosylation augments CD16-mediated serial killing and IFN gamma secretion by human natural killer cells, Frontiers in Immunology, Vol: 12, Pages: 1-14, ISSN: 1664-3224
One mechanism by which monoclonal antibodies (mAb) help treat cancer or autoimmune disease is through triggering antibody-dependent cellular cytotoxicity (ADCC) via CD16 on Natural Killer (NK) cells. Afucosylation is known to increase the affinity of mAbs for CD16 on NK cells and here, we set out to assess how mAb afucosylation affects the dynamics of NK cell interactions, receptor expression and effector functions. An IgG1 version of a clinically important anti-CD20 mAb was compared to its afucosylated counterpart (anti-CD20-AF). Opsonization of CD20-expressing target cells, 721.221 or Daudi, with anti-CD20-AF increased NK cell cytotoxicity and IFNγ secretion, compared to anti-CD20. The afucosylated mAb also caused a more rapid and greater loss of CD16 from NK cell surfaces. Loss of CD16 has recently been shown to be important for NK cell detachment and sequential engagement of multiple target cells. Here, live-cell time-lapse microscopy of individual cell-cell interactions in an aqueous environment and a three-dimensional matrix, revealed that anti-CD20-AF induced more rapid killing of opsonized target cells. In addition, NK cells detached more quickly from target cells opsonized with anti-CD20-AF compared to anti-CD20, which increased engagement of multiple targets and enabled a greater proportion of NK cells to perform serial killing. Inhibition of CD16 shedding with TAPI-0 led to reduced detachment and serial killing. Thus, disassembly of the immune synapse caused by loss of cell surface CD16 is a factor determining the efficiency of ADCC and antibody afucosylation alters the dynamics of intercellular interactions to boost serial killing.
Ambrose AR, Dechantsreiter S, Shah R, et al., 2020, Corrected Super-Resolution Microscopy Enables Nanoscale Imaging of Autofluorescent Lung Macrophages, BIOPHYSICAL JOURNAL, Vol: 119, Pages: 2403-2417, ISSN: 0006-3495
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- Citations: 1
Bonavita E, Bromley CP, Jonsson G, et al., 2020, Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade, IMMUNITY, Vol: 53, Pages: 1215-+, ISSN: 1074-7613
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- Citations: 77
Oldham MA, Slooter AJC, Cunningham C, et al., 2020, Characterising neuropsychiatric disorders in patients with COVID-19, LANCET PSYCHIATRY, Vol: 7, Pages: 932-933, ISSN: 2215-0374
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- Citations: 3
Gritsenko A, Yu S, Martin-Sanchez F, et al., 2020, Priming Is Dispensable for NLRP3 Inflammasome Activation in Human MonocytesIn Vitro, FRONTIERS IN IMMUNOLOGY, Vol: 11, ISSN: 1664-3224
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- Citations: 60
Ambrose AR, Hazime KS, Worboys JD, et al., 2020, Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 23717-23720, ISSN: 0027-8424
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- Citations: 23
Simmonds P, Friedman D, Hale A, et al., 2020, Natural Killer cell immune synapse formation and cytotoxicity is controlled by mechanical tension of the target, Annual Meeting of the American-Association-of-Immunologists - Immunology 2020, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Smith SL, Kennedy PR, Stacey KB, et al., 2020, Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing, BLOOD ADVANCES, Vol: 4, Pages: 1388-1406, ISSN: 2473-9529
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- Citations: 71
Leung EYL, Ennis D, Kennedy PR, et al., 2020, NK cells augment oncolytic adenovirus cytotoxicity in ovarian cancer, Molecular Therapy - Oncolytics, Vol: 16, Pages: 289-301, ISSN: 2372-7705
Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses—the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)—to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.
Williamson DJ, Burn GL, Simoncelli S, et al., 2020, Machine learning for cluster analysis of localization microscopy data, NATURE COMMUNICATIONS, Vol: 11
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- Citations: 27
Gritsenko A, Yu S, Martin-Sanchez F, et al., 2020, Priming is dispensable for NLRP3 inflammasome activation in human monocytes
<jats:title>ABSTRACT</jats:title><jats:p>Interleukin (IL)-1 family of cytokines modulate immune responses during infection and inflammation. IL-18 and IL-1β are members of the IL-1 family, which contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer’s disease. IL-18 and IL-1β are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. Canonical NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1β gene upregulation, and also NLRP3 post-translational licencing. A subsequent activation step leads to the assembly of the inflammasome and the cleavage of pro-IL-18 and pro-IL-1β by caspase-1 into their mature forms, allowing their release. Here we show that in primary human monocytes, the initial priming step is dispensable to form an active NLRP3 inflammasome. We found that, in the absence of priming, the NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18. Another IL-1 family member, IL-37, is constitutively cleaved but the release of its mature form was mediated by inflammasome activation, also in the absence of a priming step. This NLRP3 activation was characterised by ASC oligomerisation as well as caspase-1 and GSDMD cleavage and was blocked by the NLRP3 inhibitor MCC950 and in NLRP3 deficient cells. IL-18 and IL-37 release were impaired in GSDMD deficient THP-1s, suggesting that pyroptosis is required for release of these cytokines. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming and hence contribute to sterile inflammatory processes in health and disease.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>The NLRP3 inflammasome is a driver of inflammation through the processing of Interleukins (IL)-1β and IL-18. Hum
Kennedy PR, Barthen C, Williamson DJ, et al., 2019, Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors, SCIENCE SIGNALING, Vol: 12, ISSN: 1945-0877
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- Citations: 7
Kolba MD, Dudka W, Zareba-Koziol M, et al., 2019, Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells, CELL DEATH & DISEASE, Vol: 10, ISSN: 2041-4889
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- Citations: 40
Kennedy PR, Barthen C, Williamson DJ, et al., 2019, HLA-B and HLA-C differ in their nanoscale organization at cell surfaces, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224
The particular HLA class I variants an individual carries influences their resistance and susceptibility to a multitude of diseases. Expression level and variation in the peptide binding region correlates with, for example, a person's progression to AIDS after HIV infection. One factor which has not yet been addressed is whether or not different HLA class I proteins organize differently in the cell membrane on a nanoscale. Here, we examined the organization of three HLA-B allotypes (B*2705, B*5301, and B*5701) and two HLA-C allotypes (C*0602 and C*0702) in the membrane of 721.221 cells which otherwise lack expression of HLA-B or HLA-C. All these allotypes are ligands for the T cell receptor and leukocyte immunoglobulin-like receptors, but additionally, the HLA-B allotypes are ligands for the killer-cell immunoglobulin-like receptor family member KIR3DL1, HLA-C*0602 is a ligand for KIR2DL1, and HLA-C*0702 is a ligand for KIR2DL2/3. Using super-resolution microscopy, we found that both HLA-B and HLA-C formed more clusters and a greater proportion of HLA contributed to clusters, when expressed at lower levels. Thus, HLA class I organization is a covariate in genetic association studies of HLA class I expression level with disease progression. Surprisingly, we also found that HLA-C was more clustered than HLA-B when expression level was controlled. HLA-C consistently formed larger and more numerous clusters than HLA-B and a greater proportion of HLA-C contributed to clusters than for HLA-B. We also found that the organization of HLA class I proteins varied with cell type. T cells exhibited a particularly clustered organization of HLA class I while B cells expressed a more uniform distribution. In summary, HLA class I variants are organized differently in the cell surface membrane which may impact their functions.
Walwyn-Brown K, Guldevall K, Saeed M, et al., 2018, Human NK Cells Lyse Th2-Polarizing Dendritic Cells via NKp30 and DNAM-1, JOURNAL OF IMMUNOLOGY, Vol: 201, Pages: 2028-2041, ISSN: 0022-1767
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- Citations: 11
Gil-Krzewska A, Saeed MB, Oszmiana A, et al., 2018, An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 142, Pages: 914-+, ISSN: 0091-6749
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- Citations: 27
Srpan K, Ambrose A, Karampatzakis A, et al., 2018, Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells, JOURNAL OF CELL BIOLOGY, Vol: 217, Pages: 3267-3283, ISSN: 0021-9525
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- Citations: 75
Leung EYL, Ennis DP, Athineos D, et al., 2018, Oncolytic adenovirus infection leads to contact-dependent activation of natural killer cells and augments virotherapy effectiveness for ovarian cancer., AACR Special Conference on Addressing Critical Questions in Ovarian Cancer Research and Treatment, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 97-98, ISSN: 1078-0432
Tordo J, O'Leary C, Antunes ASLM, et al., 2018, A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency, BRAIN, Vol: 141, Pages: 2014-2031, ISSN: 0006-8950
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- Citations: 65
Davis DM, 2018, The art of medicine How studying the immune system leads us to new medicines, LANCET, Vol: 391, Pages: 2205-2206, ISSN: 0140-6736
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- Citations: 1
Davis DM, 2018, NEW INSIGHTS INTO ANTIBODY-BASED THERAPIES AND DISEASE SUSCEPTIBILITIES REVEALED BY MICROSCOPY OF HUMAN NK CELLS, Congress of the European-League-Against-Rheumatism (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 25-26, ISSN: 0003-4967
Loftus C, Saeed M, Davis D, et al., 2018, Activation of human Natural Killer cells by graphene oxide-templated antibody nanoclusters, Nano Letters: a journal dedicated to nanoscience and nanotechnology, Vol: 18, Pages: 3282-3289, ISSN: 1530-6984
An emerging new paradigm is that immune cell activation is controlled by transient interactions between supramolecular assemblies of receptors and ligands. Current immunotherapy biologic pharmaceuticals that activate or desensitize NK cells are, however, individual molecules that do not replicate this nanoscale organization of proteins. Here, we use nanoscale graphene oxide (NGO) as a template to generate soluble nanoscale clusters of Natural Killer cell-activating antibodies. We control nanocluster size and molecular number to mimic reported values for cell surface proteins. These NGO-templated molecular nanoclusters, used to stimulate NK cells via the CD16 receptor, successfully induced cellular activation, indicated by degranulation of cytolytic granules and IFN-γ secretion. Importantly, activation significantly exceeded that induced by the same antibodies applied as a solution of individual molecules. These results demonstrate that future immunotherapies could be enhanced by assembling immunomodulatory drugs into nanoclusters and establish NGO-templating as a candidate technology.
Balint S, Lopes FB, Davis DM, 2018, A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner, SCIENCE SIGNALING, Vol: 11, ISSN: 1945-0877
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- Citations: 26
Carisey AF, Mace EM, Saeed MB, et al., 2018, Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells, CURRENT BIOLOGY, Vol: 28, Pages: 489-+, ISSN: 0960-9822
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- Citations: 67
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