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Biomedicines
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The Role of NK Cells in Health and Diseases
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The Role of NK Cells in Health and Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (15 January 2025) | Viewed by 8886

Special Issue Editor

Dr. Matthew Blunt

E-Mail Website
Guest Editor
School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
Interests: NK cell activation against haematological malignancies

Special Issue Information

Dear Colleagues,

Natural killer (NK) cells possess the ability to rapidly lyse virally infected and tumour cells and promote the anti-cancer activity of other immune cell types, including macrophages, CD8+ T cells and dendritic cells. Furthermore, the development of NK cell-based therapeutics is an area of intense pre-clinical and clinical research. Importantly for their utilisation in patients, NK cell therapies are not associated with the severe toxicities that can be associated with T cell-based therapies.

Increased knowledge of the role of NK cells in health and disease will provide new avenues for research and allow for improved utilisation against pathogens and tumour cells in the clinical setting. In the following Special Issue, we invite investigators to contribute original research as well as review articles that address recent advances in NK cell function with regard to health and disease. We welcome authors to submit manuscripts that provide novel insights into NK cell biology and therapeutic strategies including CAR-NK cells, cytokines, tumour-targeting antibodies, NK cell engagers and checkpoint inhibitors.

Dr. Matthew Blunt
Guest Editor

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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • NK cells
  • lymphoma
  • multiple myeloma
  • CLL
  • AML
  • leukaemia
  • immunotherapy

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Published Papers (5 papers)

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Research

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15 pages, 3097 KiB  
Article
Differential Role of NKG2A/HLA-E Interaction in the Outcomes of Bladder Cancer Patients Treated with M. bovis BCG or Other Therapies
by Inmaculada Ruiz-Lorente, Lourdes Gimeno, Alicia López-Abad, Pedro López Cubillana, Tomás Fernández Aparicio, Lucas Jesús Asensio Egea, Juan Moreno Avilés, Gloria Doñate Iñiguez, Pablo Luis Guzmán Martínez-Valls, Gerardo Server, Belén Ferri, José Antonio Campillo, María Victoria Martínez-Sánchez and Alfredo Minguela
Biomedicines 2025, 13(1), 156; https://doi.org/10.3390/biomedicines13010156 - 10 Jan 2025
Viewed by 1133
Abstract
Background: Immunotherapy is gaining great relevance in both non-muscle-invasive bladder cancer (NMIBC), with the use of bacille Calmette–Guerin (BCG), and in muscle-invasive BC (MIBC) with anti-checkpoint therapies blocking PD-1/PD-L1, CTLA-4/CD80-CD86, and, more recently, NKG2A/HLA-E interactions. Biomarkers are necessary to optimize the use [...] Read more.
Background: Immunotherapy is gaining great relevance in both non-muscle-invasive bladder cancer (NMIBC), with the use of bacille Calmette–Guerin (BCG), and in muscle-invasive BC (MIBC) with anti-checkpoint therapies blocking PD-1/PD-L1, CTLA-4/CD80-CD86, and, more recently, NKG2A/HLA-E interactions. Biomarkers are necessary to optimize the use of these therapies. Methods: We evaluated killer-cell immunoglobulin-like receptors (KIRs) and HLA-I genotyping and the expression of NK cell receptors in circulating T and NK lymphocytes at diagnosis in 325 consecutive BC patients (151 treated with BCG and 174 treated with other therapies), as well as in 648 patients with other cancers and 973 healthy donors as controls. The proliferation and production of cytokines and cytotoxicity were evaluated in peripheral blood mononuclear cells, stimulated in vitro with anti-CD3/CD28 or BCG, from selected patients based on HLA-B −21M/T dimorphism (NKG2A ligands). Results: The HLA-B −21M/T genotype showed opposing results in BC patients treated with BCG or other therapies. The MM genotype, compared to MT and TT, was associated with a longer 75th-percentile overall survival (not reached vs. 68.0 ± 13.7 and 52.0 ± 8.3 months, p = 0.034) in BCG, but a shorter (8.0 ± 2.4 vs. 21.0 ± 3.4 and 19.0 ± 4.9 months, p = 0.131) survival in other treatments. The HLA-B −21M/T genotype was an independent predictive parameter of the progression-free survival (HR = 2.08, p = 0.01) and the OS (HR = 2.059, p = 0.039) of BC patients treated with BCG, together with age and tumor histopathologic characteristics. The MM genotype was associated with higher counts of circulating CD56bright, fewer KIR2DL1/L2+ NK cells, and lower NKG2A expression, but not with differential in vitro NK cell functionality. Conclusions: The HLA-B −21M/T is independently associated with BC patient outcomes and can help to optimize the use of new immunotherapies in these patients. Full article
(This article belongs to the Special Issue The Role of NK Cells in Health and Diseases)
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21 pages, 2792 KiB  
Article
Three-Dimensional Model Analysis Revealed Differential Cytotoxic Effects of the NK-92 Cell Line and Primary NK Cells on Breast and Ovarian Carcinoma Cell Lines Mediated by Variations in Receptor–Ligand Interactions and Soluble Factor Profiles
by Nadezhda A. Alekseeva, Anna A. Boyko, Marina A. Shevchenko, Maria V. Grechikhina, Maria A. Streltsova, Ludmila G. Alekseeva, Alexander M. Sapozhnikov, Sergey M. Deyev and Elena I. Kovalenko
Biomedicines 2024, 12(10), 2398; https://doi.org/10.3390/biomedicines12102398 - 20 Oct 2024
Viewed by 1703
Abstract
Background/objectives: The functional activity of a certain tumor determines the effectiveness of primary NK cells and NK-92 cell line-based cancer therapy; their therapeutic effectiveness against different tumors can vary. This work provides a direct simultaneous comparison of the cytotoxic effects of in vitro-activated [...] Read more.
Background/objectives: The functional activity of a certain tumor determines the effectiveness of primary NK cells and NK-92 cell line-based cancer therapy; their therapeutic effectiveness against different tumors can vary. This work provides a direct simultaneous comparison of the cytotoxic effects of in vitro-activated peripheral NK (pNK) cells and NK-92 cells in spheroid models of BT-474, MCF7 and SKOV-3 carcinomas and uncovers the reasons for the differential effectiveness of NK cells against tumors. Methods: Tumor spheroids of similar size and shape, obtained from agarose molds, were incubated with NK-92 or pNK cells for 24 h. Tumor cell death was detected using flow cytometry or confocal microscopy. Cytokine production, granzyme B levels and NK cell degranulation analyses were performed, along with pNK and target-cell phenotypic characterization. Results: While NK-92 and pNK cells lysed BT-474 spheroids with comparably low efficiency, pNK cells were more capable of eliminating MCF7 and SKOV-3 spheroids than NK-92 cells were. The results of the functional and phenotypic analyses strongly support the participation of the NKG2D-NKG2DL pathway in pNK cell activation induced by the most sensitive cytotoxic attack on SKOV-3 spheroids, whereas the CX3CR1-CX3CL1 axis appears to be involved in the pNK reaction against MCF-7 spheroids. Conclusions: We provide a new approach for the preliminary identification of the most promising NK cell receptors that can alter the effectiveness of cancer therapy depending on the specific tumor type. Using this approach, NK-92 cells or pNK subsets can be selected for further accumulation and/or genetic modification to improve specificity and reactivity. Full article
(This article belongs to the Special Issue The Role of NK Cells in Health and Diseases)
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15 pages, 3052 KiB  
Article
The Functional and Prognostic Impact of TIGIT Expression on Bone Marrow NK Cells in Core Binding Factor-Acute Myeloid Leukemia Patients at Diagnosis
by Dai-Hong Xie, Jun Wang, Kai Sun, Zong-Yan Shi, Ya-Zhe Wang, Yan Chang, Xiao-Ying Yuan, Yan-Rong Liu, Hao Jiang, Qian Jiang, Xiao-Jun Huang and Ya-Zhen Qin
Biomedicines 2024, 12(10), 2207; https://doi.org/10.3390/biomedicines12102207 - 27 Sep 2024
Viewed by 1089
Abstract
Background: The effect of the expression of the newly identified immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) on NK cells in core binding factor-acute myeloid leukemia (CBF-AML) remains to be investigated. Methods: Fresh bone marrow samples [...] Read more.
Background: The effect of the expression of the newly identified immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) on NK cells in core binding factor-acute myeloid leukemia (CBF-AML) remains to be investigated. Methods: Fresh bone marrow samples from a total of 39 newly diagnosed CBF-AML patients and 25 healthy donors (HDs) were collected for testing the phenotype and function state of total NK, CD56bright, and CD56dim NK cell subsets after in vitro stimulation. Results: The frequencies of TIGIT+ cells in total NK, CD56bright, and CD56dim NK cell subsets had no significant difference between patients and HDs. TNF-α and INF-γ levels were uniformly lower in TIGIT+ cells than the corresponding TIGIT− cells in all HDs, whereas those for TIGIT+ to TIGIT− cells in patients were highly heterogenous; TIGIT expression was not related to PFP and GZMB expression in HDs, whereas it was related to higher intracellular PFP and GZMB levels in patients. Patients’ TIGIT+ NK cells displayed lower K562 cell-killing activity than their TIGIT− NK cells. In addition, high frequencies of TIGIT+ cells in total NK and CD56dim NK cells were associated with poor RFS. Conclusions: TIGIT expression affected the diagnostic bone marrow-sited NK cell function and had prognostic significance in CBF-AML patients. Full article
(This article belongs to the Special Issue The Role of NK Cells in Health and Diseases)
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12 pages, 787 KiB  
Article
Day 100 Recovery of Absolute Number of Inhibitory KIR2DL2 and Activating NKp30 Natural Killer Cells Predicts Survival Post-Autologous Stem Cell Transplantation in Lymphomas
by Luis F. Porrata, Stephen M. Ansell, Ivana N. Micallef, Patrick B. Johnston, Jose C. Villasboas, Jonas Paludo, Urshila Durani and Svetomir N. Markovic
Biomedicines 2024, 12(8), 1808; https://doi.org/10.3390/biomedicines12081808 - 9 Aug 2024
Viewed by 1073
Abstract
The infusion autograft absolute number of inhibitory killer immunoglobulin-like receptor (KIR) 2DL2 and activating natural killer (NK)p30 cells are predictors of clinical outcomes in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). To assess if the long-term recovery of these [...] Read more.
The infusion autograft absolute number of inhibitory killer immunoglobulin-like receptor (KIR) 2DL2 and activating natural killer (NK)p30 cells are predictors of clinical outcomes in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). To assess if the long-term recovery of these NK cell subsets still holds clinical relevance, we set up to investigate their prognostic ability at day 100 post-APBHSCT. This was a retrospective single-institution study including 107 patients from our prior phase III trial who had a clinical assessment at day 100 post-APBHSCT. The median follow-up from day 100 was 168.19 months (interquartile range: 156.85–181.28 months). Patients with day 100 inhibitory KIR2DL2 < 0.08 cells/µL and activating NKp30 ≥ 0.19 cells/µL experienced superior overall survival (OS) and progression-free survival (PFS). A multivariate analysis revealed both the day 100 inhibitory KIR2DL2 [OS: HR = 1.449, 95%CI, 1.231–1.895, p < 0.013; and PFS: HR = 2.069, 95%CI, 1.134–3.775, p < 0.021] and activating NKp30 [OS: HR = 4.985, 95%CI, 2.614–9.506, p < 0.0001; and PFS: HR = 4.661, 95%CI, 2.598–8.393, p < 0.0001] were independent predictors for OS and PFS. Inhibitory KIR2DL2 and activating NKp30 NK cells at day 100 are prognostic immune biomarkers in lymphoma patients treated with APBHSCT. Full article
(This article belongs to the Special Issue The Role of NK Cells in Health and Diseases)
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Review

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15 pages, 1124 KiB  
Review
NK Cells in the Lymph Nodes and Their Role in Anti-Tumour Immunity
by Lara V. Graham, Salim I. Khakoo and Matthew D. Blunt
Biomedicines 2024, 12(8), 1667; https://doi.org/10.3390/biomedicines12081667 - 25 Jul 2024
Cited by 1 | Viewed by 3064
Abstract
The lymph nodes are vital to enable adaptive immune responses to infection. Natural killer (NK) cells are cytotoxic lymphocytes that directly kill cancer cells and modulate the activation of other immune cells during anti-tumour immune response. NK cells in the lymph nodes are [...] Read more.
The lymph nodes are vital to enable adaptive immune responses to infection. Natural killer (NK) cells are cytotoxic lymphocytes that directly kill cancer cells and modulate the activation of other immune cells during anti-tumour immune response. NK cells in the lymph nodes are involved in the regulation of T-cell and B-cell populations and the clearance of viral infections. In solid tumours, lymph nodes are a frequent site of metastasis and immune cell priming, whilst in haematological malignancies, tumour cells can proliferate in the lymph nodes. Thus, lymph nodes are an important site in anti-tumour immunity and therapy resistance. It is therefore crucial to identify strategies to increase recruitment and overcome suppression of NK cells in the lymph node microenvironment to improve tumour clearance. In this review, we summarise the literature interrogating NK cell phenotype and function in the lymph nodes in the context of infection and cancer and evaluate both current and potential strategies to mobilise and activate NK cells within the lymph nodes of cancer patients. Full article
(This article belongs to the Special Issue The Role of NK Cells in Health and Diseases)
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