Understanding natural killer cell biology from a single cell perspective

Subedi, Nikita; Verhagen, Liesbeth P.; Bosman, Esmée Michelle; Roessel, Ilse van; Tel, Jurjen

doi:10.1016/j.cellimm.2022.104497

Cited by 17 publications

(12 citation statements)

References 118 publications

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“…NK cells are fundamental for the proper protection of the liver and aberrant functions have been reported in several liver diseases. Over the past decade, studies on NK cells suggest very heterogeneous populations with distinctive transcriptomes and cellular interactions ( 64 ).…”

Section: Natural Killer Cellsmentioning

confidence: 99%

Innate immunity and early liver inflammation

Zhou

2023

Front. Immunol.

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The innate system constitutes a first-line defence mechanism against pathogens. 80% of the blood supply entering the human liver arrives from the splanchnic circulation through the portal vein, so it is constantly exposed to immunologically active substances and pathogens from the gastrointestinal tract. Rapid neutralization of pathogens and toxins is an essential function of the liver, but so too is avoidance of harmful and unnecessary immune reactions. This delicate balance of reactivity and tolerance is orchestrated by a diverse repertoire of hepatic immune cells. In particular, the human liver is enriched in many innate immune cell subsets, including Kupffer cells (KCs), innate lymphoid cells (ILCs) like Natural Killer (NK) cells and ILC-like unconventional T cells – namely Natural Killer T cells (NKT), γδ T cells and Mucosal-associated Invariant T cells (MAIT). These cells reside in the liver in a memory-effector state, so they respond quickly to trigger appropriate responses. The contribution of aberrant innate immunity to inflammatory liver diseases is now being better understood. In particular, we are beginning to understand how specific innate immune subsets trigger chronic liver inflammation, which ultimately results in hepatic fibrosis. In this review, we consider the roles of specific innate immune cell subsets in early inflammation in human liver disease.

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Section: Natural Killer Cellsmentioning

confidence: 99%

Innate immunity and early liver inflammation

Zhou

2023

Front. Immunol.

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“…4 These cells are involved in cytokine production such as IFNγ and TNF. 5 Secreted IFNγ from NK cells activates nearby immune cells to encourage antigen presentation and adaptive immune responses. 6 Despite earlier understandings that NK cells react rapidly and non-specifically to malignant cells, recent studies showed that NK cells can differentiate into adaptive cells and generate long-lived immunological memory features.…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics reveals that tumor-infiltrating natural killer cells are activated by localized ablative immunotherapy and share anti-tumor signatures induced by immune checkpoint inhibitors

Liu

Sadeghipour

Hoover

et al. 2023

Preprint

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Rationale: Natural killer (NK) cells provide protective anti-cancer immunity. However, the cancer therapy induced activation gene signatures and pathways in NK cells remain unclear. Methods: We applied a novel localized ablative immunotherapy (LAIT) by synergizing photothermal therapy (PTT) with intra-tumor delivering of the immunostimulant N-dihydrogalactochitosan (GC), to treat breast cancer using a mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) mouse model. We performed single-cell RNA sequencing (scRNAseq) analysis to unveil the cellular heterogeneity and compare the transcriptional alterations induced by PTT, GC, and LAIT in NK cells within the tumor microenvironment (TME). Results: ScRNAseq showed that NK subtypes, including cycling, activated, interferon-stimulated, and cytotoxic NK cells. Trajectory analysis revealed a route toward activation and cytotoxicity following pseudotime progression. Both GC and LAIT elevated gene expression associated with NK cell activation, cytolytic effectors, activating receptors, IFN pathway components, and cytokines/chemokines in NK subtypes. Single-cell transcriptomics analysis using immune checkpoint inhibitor (ICI)-treated animal and human samples revealed that ICI-induced NK activation and cytotoxicity across several cancer types. Furthermore, ICI-induced NK gene signatures were also induced by LAIT treatment. We also discovered that several types of cancer patients had significantly longer overall survival when they had higher expression of genes in NK cells that were also specifically upregulated by LAIT. Conclusion: Our findings show for the first time that LAIT activates cytotoxicity in NK cells and the upregulated genes positively correlate with beneficial clinical outcomes for cancer patients. More importantly, our results further establish the correlation between the effects of LAIT and ICI on NK cells, hence expanding our understanding of mechanism of LAIT in remodeling TME and shedding light on the potentials of NK cell activation and anti-tumor cytotoxic functions in clinical applications.

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“…Natural killer (NK) cells are a subgroup of type 1 innate lymphoid cells capable of inducing cytolytic activity against virus-infected immunotherapies. [10] Additionally, mass cytometry-based data demonstrated that the overall function of NK cells results from the combined efforts of multiple diverse individual cells. [11] Recent single-cell RNA sequencing-based studies identified specific markers within NK cell transcriptomes that could eventually be clustered into different functional subpopulations.…”

Section: Introductionmentioning

confidence: 99%

“…[ 6–9 ] Advancing single cell‐based technologies have allowed detailed monitoring of individual cells associating the variations within effector functions in NK cells as one of the potential reasons for lower clinical impact of NK cell‐based immunotherapies. [ 10 ] Additionally, mass cytometry‐based data demonstrated that the overall function of NK cells results from the combined efforts of multiple diverse individual cells. [ 11 ] Recent single‐cell RNA sequencing‐based studies identified specific markers within NK cell transcriptomes that could eventually be clustered into different functional subpopulations.…”

Section: Introductionmentioning

confidence: 99%

“…[ 17 ] The studies involving highly dynamic cells, such as NK cells, require efficient screening tools that could accurately identify potent cytotoxic cells among the heterogenous population and allow their characterization. [ 10 ] To meet these requirements, we have presented a high throughput droplet‐based microfluidics platform to provide a combinatorial assessment of cytotoxicity and secretory functions within the NK cell population. Here, we monitored around 80 000 droplets over 10 h in real‐time to probe the phenotypical and functional heterogeneity of single human Peripheral Blood (PB)‐NK cells and ex vivo‐generated UCB‐derived CD34+ HPCs NK cells.…”

Section: Introductionmentioning

confidence: 99%

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Single‐Cell Profiling Reveals Functional Heterogeneity and Serial Killing in Human Peripheral and Ex Vivo‐Generated CD34+ Progenitor‐Derived Natural Killer Cells

et al. 2022

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Increasing evidence suggest that Natural killer (NK) cells are composed of distinct functional subsets. This multi-functional role displayed by NK cells have made them an attractive choice for anti-cancer immunotherapy. A functional NK cell repertoire is generated through cellular education, resulting in heterogeneous NK cell population with distinct capabilities to respond to different stimuli. The application of a high-throughput droplet-based microfluidic platform allows monitoring of NK cell-target cell interactions at single-cell level and in real-time.Through fluorescence-based screening of around 80,000 droplets, with different Effector:Target ratios, a fully automated image analysis allows for the assessment of individual killing events in each droplet over time. We observed a variable response of single NK cells towards different target cells and identified a distinct population of NK cells capable of inducing multiple target lysis, coined as serial killers. To meet the increasing clinical demand for NK cells several sources, such as umbilical cord blood (UCB), have successfully been explored. By assessing the cytotoxic dynamics, we showed that single UCB-derived CD34+ hematopoietic progenitor (HPC)-NK cells display superior anti-tumor cytotoxicity.Additionally, with an integrated analysis of cytotoxicity and cytokine secretion we showed that target cell interactions augmented cytotoxic as well as secretory behavior of NK cells. By providing an in-depth assessment over NK cell functions, this study provides crucial information on diversity and functional characteristics of peripheral blood NK cells and ex vivo-generated HPC-NK cells to develop and improve of NK cell-based cancer immunotherapy.

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Understanding natural killer cell biology from a single cell perspective

Cited by 17 publications

References 118 publications

Innate immunity and early liver inflammation

Innate immunity and early liver inflammation

Single-cell transcriptomics reveals that tumor-infiltrating natural killer cells are activated by localized ablative immunotherapy and share anti-tumor signatures induced by immune checkpoint inhibitors

Single‐Cell Profiling Reveals Functional Heterogeneity and Serial Killing in Human Peripheral and Ex Vivo‐Generated CD34+ Progenitor‐Derived Natural Killer Cells

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