Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles

Ambrose, Ashley R.; Hazime, Khodor S.; Worboys, Jonathan D.; Niembro-Vivanco, Olatz; Davis, Daniel M.

doi:10.1073/pnas.2010274117

Cited by 42 publications

(38 citation statements)

References 17 publications

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“…Degranulation at the IS occurs following successful polarisation of the MTOC and lytic granules towards the NK cell-target interface. Here, granules fuse with the synaptic membrane, and their contents are expelled into the synaptic cleft as supramolecular attack particles ( Ambrose et al, 2020 ; Bálint et al, 2020 ). It is currently unclear how altering substrate stiffness impacts these different stages of NK cell activation, which lead up to secretion.…”

Section: Resultsmentioning

confidence: 99%

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

Friedman

Simmonds

Hale

et al. 2021

Journal of Cell Science

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Natural Killer (NK) cells can kill infected or transformed cells via a lytic immune synapse. Diseased cells may exhibit altered mechanical properties but how this impacts NK cell responsiveness is unknown. We report that human NK cells were stimulated more effectively to secrete granzymes A and B, FasL, granulysin and IFNγ, by stiff (142 kPa) compared to soft (1 kPa) planar substrates. To create surrogate spherical targets of defined stiffness, sodium alginate was used to synthesise soft (9 kPa), medium (34 kPa), or stiff (254 kPa) cell-sized beads, coated with antibodies against activating receptor NKp30 and the integrin LFA-1. Against stiff beads, NK cells showed increased degranulation. Polarisation of the microtubule-organising centre (MTOC) and lytic granules were impaired against soft targets, which instead resulted in the formation of unstable kinapses. Thus, by varying target stiffness to characterise the mechanosensitivity of immune synapses, we identify soft targets as a blind spot in NK cell recognition.

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Section: Resultsmentioning

confidence: 99%

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

Friedman

Simmonds

Hale

et al. 2021

Journal of Cell Science

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“…Releasing perforin and granzymes into target cell is the major molecular mechanism underlying the destroy ability of immune effector cells [17,18]. Since perforin and granzymes were exclusively secreted by immune effector cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, the expression of GZMA and PRF1 gene detected in bulk tumor tissue could be quantified as an indicator of the intra-tumoral immune CYT [19,20].…”

Section: Cyt Calculationmentioning

confidence: 99%

Benchmarking HLA genotyping and clarifying HLA impact on survival in tumor immunotherapy

Zhou

Chen

et al. 2021

Molecular Oncology

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Human Leucocyte Antigen (HLA) genotyping gains intensive attention due to its critical role in cancer immunotherapy. It is still a challenging issue to generate reliable HLA genotyping results through in silico tools. In addition, the survival impact of HLA alleles in tumor prognosis and immunotherapy remains controversial. In this study, the benchmarking of HLA genotyping on TCGA is performed and a "Gun-Bullet" model which helps to clarify the survival impact of HLA allele is presented. The performance of HLA class I genotyping is generally better than class II. POLYSOLVER, OptiType and xHLA perform generally better at HLA class I calling with an accuracy of 0.954, 0.949 and 0.937, respectively. HLA-HD obtained the highest accuracy of 0.904 on HLA class II alleles calling. Each HLA-genotyping tool displayed specific error patterns. The ensemble HLA calling from the top-3 tools is superior to any individual one. HLA alleles show distinct survival impact among cancers. Cytolytic activity (CYT) was proposed as the underlying mechanism to interpret the survival impact of HLA alleles in the "Gun-Bullet" model for fighting cancer. A strong HLA allele plus a high tumor mutation burden (TMB) could stimulate intensive immune CYT, leading to extended survival. We established an up-to-now most reliable TCGA HLA benchmark dataset, composing of concordance alleles generated from eight prevalently used HLA genotyping tools. Our findings indicate that reliable HLA genotyping should be performed based on concordance alleles integrating multiple tools and incorporating TMB background with HLA genotype, which helps to improve the survival prediction compared to HLA genotyping alone.

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“…NK cell activation is controlled by the balance of signals from a variety of germline encoded activating and inhibitory receptors ( 1 ). Upon activation, NK cells can directly kill diseased cells by secretion of lytic granules that typically contain pore-forming perforin and lytic granzymes ( 2 , 3 ). NK cells also augment the immune response by secreting immuno-stimulatory cytokines and chemokines including pro-inflammatory interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Antibody Afucosylation Augments CD16-Mediated Serial Killing and IFNγ Secretion by Human Natural Killer Cells

et al. 2021

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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.

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Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles

Cited by 42 publications

References 17 publications

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

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

Benchmarking HLA genotyping and clarifying HLA impact on survival in tumor immunotherapy

Antibody Afucosylation Augments CD16-Mediated Serial Killing and IFNγ Secretion by Human Natural Killer Cells

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