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Cells
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Advances in the Study of Natural Killer (NK) Cells
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Advances in the Study of Natural Killer (NK) Cells

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: 25 November 2024 | Viewed by 10575

Special Issue Editors

Dr. Fuguo Liu

E-Mail Website
Guest Editor
Massachusetts Institute of Technology, Cambridge, MA, USA
Interests: NK cell biology; MHC I; cancer immunotherapy
Dr. Mubin Tarannum

E-Mail Website
Guest Editor
Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Interests: genetically engineered NK cells; CAR NK cells; memory-like NK cells
Dr. Yingjie Zhao

E-Mail Website
Guest Editor
Massachusetts Institute of Technology, Cambridge, MA, USA
Interests: CAR-NK; cancer neoantigen; antibody; scFv; MHC I

Special Issue Information

Dear Colleagues,

Natural killer cells, identified by the expression of CD56 and lacking CD3 expression, are innate lymphocytes that can kill virally infected cells and tumor cells. Specialized NK cells are found in the placenta and may play critical roles during pregnancy. NK cell activation is controlled by a set of germline-encoded activating and inhibitory receptors, such as killer cell receptors (KIRs), natural cytotoxicity receptors (NCRs), DNAM, and TIGIT. In addition, CD16 expression on NK cells can also mediate antibody-dependent cellular cytotoxicity. Furthermore, NK cells can express a large range of cytokines that regulate the development of other types of cells.

Because NK cells exhibit potent anti-tumor immunity through multiple mechanisms, they have attracted increased interest in being used in cancer immunotherapy. Compared to chimeric antigen receptor (CAR) T cells, CAR-NK cells have some significant advantages, including (1) better safety, such as a lack or minimal cytokine release syndrome and neurotoxicity; (2) multiple mechanisms for NK cell activation, so we have more room to enhance NK cell cytotoxicity; and (3) a high potential for ‘off-the-shelf’ manufacturing.

This Special Issue of Cells will highlight NK cell biology and the application of NK cells in cancer immunotherapy through a collection of original research articles, reviews, and communications. We welcome studies related to this topic to be submitted to this Special Issue in order to promote the development of NK cell studies.

Dr. Fuguo Liu
Dr. Mubin Tarannum
Dr. Yingjie Zhao
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural killer cells
  • chimeric antigen receptor
  • immunotherapy
  • activating receptors
  • inhibitory receptors

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Published Papers (4 papers)

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Research

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21 pages, 2984 KiB  
Article
Analysis of Cytotoxic Granules and Constitutively Produced Extracellular Vesicles from Large Granular Lymphocytic Leukemia Cell Lines
by Lara Ploeger, Patrick Kaleja, Andreas Tholey, Marcus Lettau and Ottmar Janssen
Cells 2024, 13(16), 1310; https://doi.org/10.3390/cells13161310 - 6 Aug 2024
Viewed by 916
Abstract
Background: Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and [...] Read more.
Background: Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and include, e.g., neutropenia, anemia, recurrent infections, and autoimmunity. A limited number of available patient-derived cell lines are considered valuable tools to study the biology of these malignancies. They differ in the expression of lineage-specific surface markers, but generally contain cytotoxic effector molecules in characteristic granules. Methods: We investigated the presence and release of lysosome-associated effector proteins in patient-derived LGLL cell lines by flow and imaging cytometry, by Western blotting and by bottom–up proteomics profiling. Results: The tested cell lines did not express FasL (CD178), but did express CD26/DPP4+. Intracellularly, we detected major differences in the abundance and subcellular distribution of granzymes, perforin, and granulysin. Similar differences were seen in enriched lysosome-related effector vesicles (LREVs). The proteomics profiling of enriched EVs from an NK-LGLL line (NKL) and a T-LGLL line (MOTN-1), confirmed individual profiles of effector molecules. Conclusion: Our analyses underscore the individual distribution of effector proteins but also open new routes to define the role of intra- and extracellular granules in the disease manifestation or pathology of LGLLs. Full article
(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)
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29 pages, 4113 KiB  
Article
A Critical Role of Culture Medium Selection in Maximizing the Purity and Expansion of Natural Killer Cells
by Neele Kusch, Jonathan Storm, Antonia Macioszek, Ella Kisselmann, Cornelius Knabbe, Barbara Kaltschmidt and Christian Kaltschmidt
Cells 2024, 13(13), 1148; https://doi.org/10.3390/cells13131148 - 5 Jul 2024
Viewed by 1839
Abstract
Natural killer (NK) cells hold promise in cancer treatment due to their ability to spontaneously lyse cancer cells. For clinical use, high quantities of pure, functional NK cells are necessary. Combining adherence-based isolation with specialized media showed the unreliability of the isolation method, [...] Read more.
Natural killer (NK) cells hold promise in cancer treatment due to their ability to spontaneously lyse cancer cells. For clinical use, high quantities of pure, functional NK cells are necessary. Combining adherence-based isolation with specialized media showed the unreliability of the isolation method, but demonstrated the superiority of the NK MACS® medium, particularly in suboptimal conditions. Neither human pooled serum, fetal calf serum (FCS), human platelet lysate, nor chemically defined serum replacement could substitute human AB serum. Interleukin (IL-)2, IL-15, IL-21, and combined CD2/NKp46 stimulation were assessed. IL-21 and CD2/NKp46 stimulation increased cytotoxicity, but reduced NK cell proliferation. IL-15 stimulation alone achieved the highest proliferation, but the more affordable IL-2 performed similarly. The RosetteSep™ human NK cell enrichment kit was effective for isolation, but the presence of peripheral blood mononuclear cells (PBMCs) in the culture enhanced NK cell proliferation, despite similar expression levels of CD16, NKp46, NKG2D, and ICAM-1. In line with this, purified NK cells cultured in NK MACS® medium with human AB serum and IL-2 demonstrated high cytotoxicity against primary glioblastoma stem cells. Full article
(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)
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Review

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16 pages, 1532 KiB  
Review
Maintaining the Balance: Regulation of NK Cell Activity
by Vanna Imširović, Felix M. Wensveen, Bojan Polić and Vedrana Jelenčić
Cells 2024, 13(17), 1464; https://doi.org/10.3390/cells13171464 - 31 Aug 2024
Viewed by 1042
Abstract
Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather [...] Read more.
Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather than depending on the engagement of a single activating receptor, their activation involves a delicate balance between inhibitory and activating signals mediated through an array of surface molecules. Only when this cumulative balance surpasses a specific threshold do NK cells initiate their activity. Remarkably, the activation threshold of NK cells remains robust even when cells express vastly different repertoires of inhibitory and activating receptors. These threshold values seem to be influenced by NK cell interactions with their environment during development and after release from the bone marrow. Understanding how NK cells integrate this intricate pattern of stimuli is an ongoing area of research, particularly relevant for cellular therapies seeking to harness the anti-cancer potential of these cells by modifying surface receptor expression. In this review, we will explore some of the current dogmas regarding NK cell activation and discuss recent literature addressing advances in our understanding of this field. Full article
(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)
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21 pages, 1846 KiB  
Review
Building a Better Defense: Expanding and Improving Natural Killer Cells for Adoptive Cell Therapy
by Andreia Maia, Mubin Tarannum, Joana R. Lérias, Sara Piccinelli, Luis Miguel Borrego, Markus Maeurer, Rizwan Romee and Mireia Castillo-Martin
Cells 2024, 13(5), 451; https://doi.org/10.3390/cells13050451 - 5 Mar 2024
Cited by 4 | Viewed by 6207
Abstract
Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even [...] Read more.
Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even in an allogeneic setting. Despite this tremendous potential, challenges persist, such as limited in vivo persistence, reduced tumor infiltration, and low absolute NK cell numbers. This review outlines several strategies aiming to overcome these challenges. The developed strategies include optimizing NK cell expansion methods and improving NK cell antitumor responses by cytokine stimulation and genetic manipulations. Using K562 cells expressing membrane IL-15 or IL-21 with or without additional activating ligands like 4-1BBL allows “massive” NK cell expansion and makes multiple cell dosing and “off-the-shelf” efforts feasible. Further improvements in NK cell function can be reached by inducing memory-like NK cells, developing chimeric antigen receptor (CAR)-NK cells, or isolating NK-cell-based tumor-infiltrating lymphocytes (TILs). Memory-like NK cells demonstrate higher in vivo persistence and cytotoxicity, with early clinical trials demonstrating safety and promising efficacy. Recent trials using CAR-NK cells have also demonstrated a lack of any major toxicity, including cytokine release syndrome, and, yet, promising clinical activity. Recent data support that the presence of TIL-NK cells is associated with improved overall patient survival in different types of solid tumors such as head and neck, colorectal, breast, and gastric carcinomas, among the most significant. In conclusion, this review presents insights into the diverse strategies available for NK cell expansion, including the roles played by various cytokines, feeder cells, and culture material in influencing the activation phenotype, telomere length, and cytotoxic potential of expanded NK cells. Notably, genetically modified K562 cells have demonstrated significant efficacy in promoting NK cell expansion. Furthermore, culturing NK cells with IL-2 and IL-15 has been shown to improve expansion rates, while the presence of IL-12 and IL-21 has been linked to enhanced cytotoxic function. Overall, this review provides an overview of NK cell expansion methodologies, highlighting the current landscape of clinical trials and the key advancements to enhance NK-cell-based adoptive cell therapy. Full article
(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)
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