Publications
191 results found
Sheppard S, Srpan K, Lin W, et al., 2024, Fatty acid oxidation fuels natural killer cell responses against infection and cancer., Proc Natl Acad Sci U S A, Vol: 121
Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.
Patterson C, Hazime K, Zelenay S, et al., 2024, Prostaglandin E₂ impacts multiple stages of the natural killer cell antitumor immune response, European Journal of Immunology, Vol: 54, ISSN: 0014-2980
Tumor immune escape is a major factor contributing to cancer progression and unresponsiveness to cancer therapies. Tumors can produce prostaglandin E2 (PGE2), an inflammatory mediator that directly acts on Natural killer (NK) cells to inhibit antitumor immunity. However, precisely how PGE2 influences NK cell tumor-restraining functions remains unclear. Here, we report that following PGE₂ treatment, human NK cells exhibited altered expression of specific activating receptors and a reduced ability to degranulate and kill cancer targets. Transcriptional analysis uncovered that PGE₂ also differentially modulated the expression of chemokine receptors by NK cells, inhibiting CXCR3 but increasing CXCR4. Consistent with this, PGE₂-treated NK cells exhibited decreased migration to CXCL10 but increased ability to migrate toward CXCL12. Using live cell imaging, we showed that in the presence of PGE2, NK cells were slower and less likely to kill cancer target cells following conjugation. Imaging the sequential stages of NK cell killing revealed that PGE₂ impaired NK cell polarization, but not the re-organization of synaptic actin or the release of perforin itself. Together, these findings demonstrate that PGE₂ affects multiple but select NK cell functions. Understanding how cancer cells subvert NK cells is necessary to more effectively harness the cancer-inhibitory function of NK cells in treatments.
Worboys JD, Davis DM, 2024, Do inhibitory receptors need to be proximal to stimulatory receptors to function?, Genes Immun
Sasidharan S, Davis DM, Dunlop IE, 2023, Bioinspired Materials for Immunoengineering of T Cells and Natural Killer Cells, ADVANCED FUNCTIONAL MATERIALS, ISSN: 1616-301X
Davis D, Worboys J, Vowell K, et al., 2023, TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation, Nature Communications, Vol: 14, ISSN: 2041-1723
TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
Ambrose AR, Hazime KS, Davis DM, 2023, Analyzing Single Cell Secretions by "Shadow Imaging"., Methods Mol Biol, Vol: 2654, Pages: 409-420
Here, we describe a method, which we term "shadow imaging," to analyze the secretions of individual cells at immune synapses or other cell contacts. Following immune synapse formation and cellular activation on ligand-rich slides, the position of each cell is recorded using a pulsed immunofluorescence stain against the proteins on the ligand-rich slide surface. The pulsed stain does not penetrate the synaptic cleft, resulting in an unlabeled region or "shadow" beneath cells that is retained following cellular detachment. The secreted components, such as perforin, exosomes, or other types of extracellular vesicles, are retained on the slide and can be analyzed on a single-cell basis using immunofluorescence. The ability to identify single cells secreting different combinations of particles, proteins, and vesicles enables us to better understand the heterogeneity in immune cell secretions and can be used as a novel approach for phenotyping cell populations.
Davis DM, 2022, The Secret Body How the New Science of the Human Body Is Changing the Way We Live, Publisher: National Geographic Books, ISBN: 9781529110975
Welcome to a revolution in the science of human health… This book takes us to the frontier of medical research and reveals stunning recent advances that are changing our understanding of how human body works, how we combat and prevent ...
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: 11
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.
Davis D, 2022, Questioning cultures, Biologist, Vol: 69, Pages: 2-3, ISSN: 0006-3347
Culture was once thought to be specifically human, but recently there have been many discoveries relating to social learning in animals. This issue includes an article by Andrew Whitten FRSB on this topic, detailing how local ‘cultures’ influence the lives of mammals, birds, fish and even insects.
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: 11
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-1β Secretion in Human Macrophages, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
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- Citations: 9
Gritsenko A, Yu S, Martin-Sanchez F, et al., 2021, Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes <i>In Vitro</i> (vol 11,565924, 2020), FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
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- Citations: 2
Davis DM, 2021, Engineering immunity, NEW SCIENTIST, Vol: 245, Pages: 40-43, ISSN: 0262-4079
Davis DM, 2021, Engineering immunity, New Scientist, Vol: 250, Pages: 40-43, ISSN: 0262-4079
Antibodies are a vital weapon in our immune system's arsenal. Now we can redesign them from scratch to better fight disease, says immunologist Daniel M. Davis
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: 15
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.
Davis D, 2021, A whole new world, Biologist, Vol: 68, Pages: 14-17, ISSN: 0006-3347
An exclusive extract from Professor Dan Davis’s new book, The Secret Body, explains how super-resolution microscopy is revealing the workings of cells in “magical and humbling” new detail.
Davis D, 2021, How we’ve missed the power of museums, Biologist, Vol: 68, Pages: 2-3, ISSN: 0006-3347
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: 98
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: 2
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 Monocytes<i>In Vitro</i>, FRONTIERS IN IMMUNOLOGY, Vol: 11, ISSN: 1664-3224
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- Citations: 73
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: 29
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: 87
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.
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