Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
9.9
5.1
Journals
Cells
Special Issues
New Developments of Natural Killer (NK) Cells in Immunotherapy
share announcement

New Developments of Natural Killer (NK) Cells in Immunotherapy

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 45131

Special Issue Editors

Dr. Jacques Zimmer

E-Mail Website
Guest Editor
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, 29 rue Henri Koch 4354, Luxembourg
Interests: natural killer cells; immunotherapy; MAIT cells; HLA class I deficiency
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Vladimir Jurisic

E-Mail Website
Guest Editor
Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
Interests: innate immunity; NK cells; cytokines; immunomodulation; oncology; hematology; biochemistry; tumor markers; molecular markers; polymorphisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Most of the first natural killer (NK) cell papers in the 1970s described a cytolytic effect on various tumor cell lines, so the idea of using NK cells in immunotherapy of cancer rapidly came up. However, success in the clinical settings was very limited. Four decades later, the therapeutic possibilities given by these cells have reached an unanticipated level of sophistication and diversity that goes in parallel with a steadily increasing knowledge about NK cell biology. Even if they are mistakenly less considered than chimeric antigen receptor (CAR)-T cells, NK cells have become a serious option for cancer treatment, although by far not all problems are resolved. The interest of the scientific community is highlighted by the increasing number of reviews about this topic. In the present Special Issue of Cells, experts in the field will describe the state-of-the-art in NK cell-based immunotherapy in 2020, based on their own expertise and on literature published in recent years.

Dr. Jacques Zimmer
Prof. Dr. Vladimir Jurisic
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
  • immunotherapy
  • leukemia and lymphoma
  • solid tumors
  • infectious diseases
  • tumor microenvironment

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (8 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

3 pages, 203 KiB  
Editorial
Special Issue “New Developments in Natural Killer Cells for Immunotherapy”
by Jacques Zimmer and Vladimir Jurišić
Cells 2023, 12(11), 1496; https://doi.org/10.3390/cells12111496 - 29 May 2023
Cited by 12 | Viewed by 1371
Abstract
Since their formal discovery in 1975, natural killer (NK) cells have always been proposed in the literature as a potential treatment for cancer and viral infections [...] Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)

Research

Jump to: Editorial, Review

14 pages, 2442 KiB  
Article
NK and T Cell Immunological Signatures in Hospitalized Patients with COVID-19
by Laura Bergantini, Miriana d'Alessandro, Paolo Cameli, Dalila Cavallaro, Sara Gangi, Behar Cekorja, Piersante Sestini and Elena Bargagli
Cells 2021, 10(11), 3182; https://doi.org/10.3390/cells10113182 - 15 Nov 2021
Cited by 23 | Viewed by 4198
Abstract
Severe acute respiratory syndrome caused by coronavirus 2 emerged in Wuhan (China) in December 2019 and has severely challenged the human population. NK and T cells are involved in the progression of COVID-19 infection through the ability of NK cells to modulate T-cell [...] Read more.
Severe acute respiratory syndrome caused by coronavirus 2 emerged in Wuhan (China) in December 2019 and has severely challenged the human population. NK and T cells are involved in the progression of COVID-19 infection through the ability of NK cells to modulate T-cell responses, and by the stimulation of cytokine release. No detailed investigation of the NK cell landscape in clinical SARS-CoV-2 infection has yet been reported. A total of 35 COVID-19 hospitalised patients were stratified for clinical severity and 17 healthy subjects were enrolled. NK cell subsets and T cell subsets were analysed with flow cytometry. Serum cytokines were detected with a bead-based multiplex assay. Fewer CD56dimCD16brightNKG2A+NK cells and a parallel increase in the CD56+CD69+NK, CD56+PD-1+NK, CD56+NKp44+NK subset were reported in COVID-19 than HC. A significantly higher adaptive/memory-like NK cell frequency in patients with severe disease than in those with mild and moderate phenotypes were reported. Moreover, adaptive/memory-like NK cell frequencies were significantly higher in patients who died than in survivors. Severe COVID-19 patients showed higher serum concentrations of IL-6 than mild and control groups. Direct correlation emerged for IL-6 and adaptive/memory-like NK. All these findings provide new insights into the immune response of patients with COVID-19. In particular, they demonstrate activation of NK through overexpression of CD69 and CD25 and show that PD-1 inhibitory signalling maintains an exhausted phenotype in NK cells. These results suggest that adaptive/memory-like NK cells could be the basis of promising targeted therapy for future viral infections. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Graphical abstract

22 pages, 25479 KiB  
Article
In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment
by Stefan Grote, Guillermo Ureña-Bailén, Kenneth Chun-Ho Chan, Caroline Baden, Markus Mezger, Rupert Handgretinger and Sabine Schleicher
Cells 2021, 10(5), 1020; https://doi.org/10.3390/cells10051020 - 26 Apr 2021
Cited by 23 | Viewed by 4798
Abstract
Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent [...] Read more.
Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Figure 1

16 pages, 2305 KiB  
Article
Anti-PSMA CAR-Engineered NK-92 Cells: An Off-the-Shelf Cell Therapy for Prostate Cancer
by Isabella Monia Montagner, Alessandro Penna, Giulio Fracasso, Debora Carpanese, Anna Dalla Pietà, Vito Barbieri, Gaia Zuccolotto and Antonio Rosato
Cells 2020, 9(6), 1382; https://doi.org/10.3390/cells9061382 - 2 Jun 2020
Cited by 55 | Viewed by 7198
Abstract
Prostate cancer (PCa) has become the most common cancer among males in Europe and the USA. Adoptive immunotherapy appears a promising strategy to control the advanced stages of the disease by specifically targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) [...] Read more.
Prostate cancer (PCa) has become the most common cancer among males in Europe and the USA. Adoptive immunotherapy appears a promising strategy to control the advanced stages of the disease by specifically targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a novel therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. More importantly, the potential utility of NK-92/CAR cells to treat PCa has not yet been explored. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable, and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Figure 1

20 pages, 3728 KiB  
Article
Directed Differentiation of Mobilized Hematopoietic Stem and Progenitor Cells into Functional NK Cells with Enhanced Antitumor Activity
by Pranav Oberoi, Kathrina Kamenjarin, Jose Francisco Villena Ossa, Barbara Uherek, Halvard Bönig and Winfried S. Wels
Cells 2020, 9(4), 811; https://doi.org/10.3390/cells9040811 - 27 Mar 2020
Cited by 18 | Viewed by 6827
Abstract
Obtaining sufficient numbers of functional natural killer (NK) cells is crucial for the success of NK-cell-based adoptive immunotherapies. While expansion from peripheral blood (PB) is the current method of choice, ex vivo generation of NK cells from hematopoietic stem and progenitor cells (HSCs) [...] Read more.
Obtaining sufficient numbers of functional natural killer (NK) cells is crucial for the success of NK-cell-based adoptive immunotherapies. While expansion from peripheral blood (PB) is the current method of choice, ex vivo generation of NK cells from hematopoietic stem and progenitor cells (HSCs) may constitute an attractive alternative. Thereby, HSCs mobilized into peripheral blood (PB-CD34+) represent a valuable starting material, but the rather poor and donor-dependent differentiation of isolated PB-CD34+ cells into NK cells observed in earlier studies still represents a major hurdle. Here, we report a refined approach based on ex vivo culture of PB-CD34+ cells with optimized cytokine cocktails that reliably generates functionally mature NK cells, as assessed by analyzing NK-cell-associated surface markers and cytotoxicity. To further enhance NK cell expansion, we generated K562 feeder cells co-expressing 4-1BB ligand and membrane-anchored IL-15 and IL-21. Co-culture of PB-derived NK cells and NK cells that were ex-vivo-differentiated from HSCs with these feeder cells dramatically improved NK cell expansion, and fully compensated for donor-to-donor variability observed during only cytokine-based propagation. Our findings suggest mobilized PB-CD34+ cells expanded and differentiated according to this two-step protocol as a promising source for the generation of allogeneic NK cells for adoptive cancer immunotherapy. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Figure 1

26 pages, 2092 KiB  
Article
Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy
by Loris Zamai, Genny Del Zotto, Flavia Buccella, Sara Gabrielli, Barbara Canonico, Marco Artico, Claudio Ortolani and Stefano Papa
Cells 2020, 9(3), 753; https://doi.org/10.3390/cells9030753 - 19 Mar 2020
Cited by 25 | Viewed by 6344
Abstract
The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited [...] Read more.
The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

35 pages, 1449 KiB  
Review
Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity
by Alberto Mendoza-Valderrey, Maite Alvarez, Andrea De Maria, Kim Margolin, Ignacio Melero and Maria Libera Ascierto
Cells 2022, 11(19), 3147; https://doi.org/10.3390/cells11193147 - 6 Oct 2022
Cited by 5 | Viewed by 3435
Abstract
In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued [...] Read more.
In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Figure 1

27 pages, 1341 KiB  
Review
NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development
by Ali Bashiri Dezfouli, Mina Yazdi, Alan Graham Pockley, Mohammad Khosravi, Sebastian Kobold, Ernst Wagner and Gabriele Multhoff
Cells 2021, 10(12), 3390; https://doi.org/10.3390/cells10123390 - 1 Dec 2021
Cited by 20 | Viewed by 8750
Abstract
In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction [...] Read more.
In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction strongly depends on the selected tumor antigen and its expression density on cancer cells. CD19 CAR-engineered T cells approved by the Food and Drug Administration have been most frequently applied in the treatment of hematological malignancies. Clinical challenges in their application primarily include cytokine release syndrome, neurological symptoms, severe inflammatory responses, and/or other off-target effects most likely mediated by cytotoxic T cells. As a consequence, there remains a significant medical need for more potent technology platforms leveraging cell-based approaches with enhanced safety profiles. A promising population that has been advanced is the natural killer (NK) cell, which can also be engineered with CARs. NK cells which belong to the innate arm of the immune system recognize and kill virally infected cells as well as (stressed) cancer cells in a major histocompatibility complex I independent manner. NK cells play an important role in the host’s immune defense against cancer due to their specialized lytic mechanisms which include death receptor (i.e., Fas)/death receptor ligand (i.e., Fas ligand) and granzyme B/perforin-mediated apoptosis, and antibody-dependent cellular cytotoxicity, as well as their immunoregulatory potential via cytokine/chemokine release. To develop and implement a highly effective CAR NK cell-based therapy with low side effects, the following three principles which are specifically addressed in this review have to be considered: unique target selection, well-designed CAR, and optimized gene delivery. Full article
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-8
Back to TopTop