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Development and Function of Natural Killer Cells and their Importance in Immunotherapy

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 54177

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Special Issue Editors

Dr. Cinzia Fionda

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Guest Editor

Department of Molecular Medicine, University of Rome "Sapienza", 00161 Rome, Italy
Interests: innate immunity; NK cells; regulation of NK cell activating ligands; anti-tumor immune response; NK cells and multiple myeloma
Special Issues, Collections and Topics in MDPI journals

Dr. Helena Stabile

E-Mail Website
Guest Editor

Department of Molecular Medicine, University of Rome "Sapienza", 00161 Rome, Italy
Interests: innate immunity; NK cell subsets; NK cell migration; NK cells in haematological diseases; NK cells and bone marrow transplantation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Major efforts are aimed at developing immunotherapeutic strategies for cancer. Particular attention has been given to the therapeutic potential of natural killer (NK) cells, which are important effectors and regulators of anti-tumor immune response. They exert cytotoxicity against malignant cells, but are also an important source of chemokines and cytokines, which are highly impacting on adaptive immune responses. Increasing evidence shows the extreme heterogeneity and plasticity of NK cell populations, implying that different NK cell subsets, endowed with specific phenotypic and functional features, may be involved and play distinct roles in the tumor context. Indeed, the tumor microenvironment modulates NK cells, rendering them functionally impaired and/or altered.Various strategies have been proposed to exploit or restore NK cell anti-tumor properties, with promising results in clinical trials.

This Special Issue will focus on the relevance of NK cell activity in solid and haematological cancer. We invite authors/investigators to publish original research articles and review articles on the mechanisms impacting the function and development of these innate lymphocytes in the tumor microenvironment. A better understanding of these complex mechanisms will contribute to the development of new NK-cell-based strategies against cancer.

Potential topics include, but are not limited to the following:

NK cell subsets in cancer
Impact of tumor microenvironment on NK cell function and/or development
Plasticity of NK cells in cancer
NK-cell based immunotherapies against cancer

Dr. Cinzia Fionda
Dr. Helena Stabile
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. Journal of Clinical Medicine 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 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
Immunotherapy
Tumor microenvironment

Published Papers (10 papers)

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Research

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10 pages, 1745 KiB

Open AccessCommunication

NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells

by Helena Stabile, Paolo Nisti, Cinzia Fionda, Daria Pagliara, Stefania Gaspari, Franco Locatelli, Angela Santoni and Angela Gismondi

J. Clin. Med. 2019, 8(11), 1904; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111904 - 07 Nov 2019

Cited by 3 | Viewed by 2447

Abstract

T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56^lowCD16^low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56^lowCD16^low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56^lowCD16^low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56^lowCD16^low NK cells in the T-cell-depleted haplo-HSC transplanted patients. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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14 pages, 2390 KiB

Open AccessArticle

NT5E/CD73 as Correlative Factor of Patient Survival and Natural Killer Cell Infiltration in Glioblastoma

by Jiao Wang and Sandro Matosevic

J. Clin. Med. 2019, 8(10), 1526; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8101526 - 23 Sep 2019

Cited by 30 | Viewed by 4080

Abstract

CD73, a cell-surface protein encoded by the gene NT5E, is overexpressed in glioblastoma (GBM), where it contributes to the tumor’s pathophysiology via the generation of immunosuppressive adenosine. Adenosinergic signaling, in turn, drives immunosuppression of natural killer (NK) cells through metabolic and functional reprogramming. The correlation of CD73 with patient survival in relation to GBM pathology and the intratumoral infiltration of NK cells has not been comprehensively studied before. Here, we present an analysis of the prognostic relevance of CD73 in GBM based on transcriptional gene expression from patient data from The Cancer Genome Atlas (TCGA) database. Utilizing bioinformatics data mining tools, we explore the relationship between GBM prognosis, NT5E expression, and intratumoral presence of NK cells. Our analysis demonstrates that CD73 is a negative prognostic factor for GBM and that presence of NK cells may associate with improved prognosis. Moreover, the interplay between expression of NT5E and specific NK genes hints to potential functional effects of CD73 on NK cell activation. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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17 pages, 3319 KiB

Open AccessArticle

Indoleamine-2,3-Dioxygenase in Thyroid Cancer Cells Suppresses Natural Killer Cell Function by Inhibiting NKG2D and NKp46 Expression via STAT Signaling Pathways

by Arum Park, Yunjeong Yang, Yunhee Lee, Mi Sun Kim, Young-Jun Park, Haiyoung Jung, Tae-Don Kim, Hee Gu Lee, Inpyo Choi and Suk Ran Yoon

J. Clin. Med. 2019, 8(6), 842; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8060842 - 12 Jun 2019

Cited by 39 | Viewed by 3937

Abstract

Natural killer (NK) cells are key players in the immune system. They use receptors on their cell surface to identify target cells. However, to escape being killed by the immune system, cancer cells such as thyroid cancer cells, use various methods to suppress the function of NK cells. Thus, this study aims to elucidate how thyroid cancer cells downregulate NK cell function in a co-culture system. We found that thyroid cancer cells suppress NK cell cytotoxicity and inhibit the expression of activating receptors, such as NKG2D and NKp46, by regulating indoleamine 2,3-dioxygenase (IDO). Also, thyroid cancer cells produce kynurenine using IDO, which causes NK cell dysfunction. Kynurenine enters NK cells via the aryl hydrocarbon receptor (AhR) on the surfaces of the NK cells, which decreases NK cell function and NK receptor expression via the signal transducer and activator of transcription (STAT) 1 and STAT3 pathways. In addition, STAT1 and STAT3 directly regulated the expression of NKG2D and NKp46 receptors by binding to the promoter region. Conclusively, NK cell function may be impaired in thyroid cancer patients by IDO-induced kynurenine production. This implies that IDO can be used as a target for thyroid cancer therapeutics aiming at improving NK cell function. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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Review

Jump to: Research

13 pages, 706 KiB

Open AccessReview

CD56bright Natural Killer Cells: A Possible Biomarker of Different Treatments in Multiple Sclerosis

by Alice Laroni and Antonio Uccelli

J. Clin. Med. 2020, 9(5), 1450; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9051450 - 13 May 2020

Cited by 25 | Viewed by 4028

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, which leads, in many cases, to irreversible disability. More than 15 disease-modifying treatments (DMTs) are available for the treatment of MS. Clinical activity or activity at magnetic resonance imaging (MRI) are now used to assess the efficacy of DMTs, but are negative prognostic factors per se. Therefore, a biomarker permitting us to identify patients who respond to treatment before they develop clinical/radiological signs of MS activity would be of high importance. The number of circulating CD56^bright natural killer (NK) cells may be such a biomarker. CD56^bright NK cells are a regulatory immune population belonging to the innate immune system. The number of CD56^bright NK cells increases upon treatment with interferon-beta, alemtuzumab, dimethyl fumarate, after autologous hematopoietic stem cell transplantation, and is higher in those who respond to fingolimod. In some cases, an increased number of CD56^bright NK cells is associated with an increase in their regulatory function. In the current review, we will evaluate the known effect on CD56^bright NK cells of DMTs for MS, and will discuss their possible role as a biomarker for treatment response in MS. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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14 pages, 576 KiB

Open AccessReview

Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

by Cinzia Fionda, Helena Stabile, Cristina Cerboni, Alessandra Soriani, Angela Gismondi, Marco Cippitelli and Angela Santoni

J. Clin. Med. 2020, 9(1), 143; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010143 - 05 Jan 2020

Cited by 19 | Viewed by 3648

Abstract

Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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35 pages, 2620 KiB

Open AccessReview

NK Cell-Based Immunotherapy for Hematological Malignancies

by Simona Sivori, Raffaella Meazza, Concetta Quintarelli, Simona Carlomagno, Mariella Della Chiesa, Michela Falco, Lorenzo Moretta, Franco Locatelli and Daniela Pende

J. Clin. Med. 2019, 8(10), 1702; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8101702 - 16 Oct 2019

Cited by 51 | Viewed by 8747

Abstract

Natural killer (NK) lymphocytes are an integral component of the innate immune system and represent important effector cells in cancer immunotherapy, particularly in the control of hematological malignancies. Refined knowledge of NK cellular and molecular biology has fueled the interest in NK cell-based antitumor therapies, and recent efforts have been made to exploit the high potential of these cells in clinical practice. Infusion of high numbers of mature NK cells through the novel graft manipulation based on the selective depletion of T cells and CD19⁺ B cells has resulted into an improved outcome in children with acute leukemia given human leucocyte antigen (HLA)-haploidentical hematopoietic transplantation. Likewise, adoptive transfer of purified third-party NK cells showed promising results in patients with myeloid malignancies. Strategies based on the use of cytokines or monoclonal antibodies able to induce and optimize NK cell activation, persistence, and expansion also represent a novel field of investigation with remarkable perspectives of favorably impacting on outcome of patients with hematological neoplasia. In addition, preliminary results suggest that engineering of mature NK cells through chimeric antigen receptor (CAR) constructs deserve further investigation, with the goal of obtaining an “off-the-shelf” NK cell bank that may serve many different recipients for granting an efficient antileukemia activity. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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13 pages, 455 KiB

Open AccessReview

NK Cell-Fc Receptors Advance Tumor Immunotherapy

by Emilio Sanseviero

J. Clin. Med. 2019, 8(10), 1667; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8101667 - 12 Oct 2019

Cited by 14 | Viewed by 5960

Abstract

Immunotherapy has revolutionized the treatment of cancer patients. Among immunotherapeutic approaches, antibodies targeting immune checkpoint inhibitors Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for treatment of metastatic melanoma and are in clinical trials for a variety of other cancers. The contribution of Natural Killer (NK) cells to the efficacy of immune checkpoint inhibitors is becoming more evident. Enhancing both T and NK cell function in cancer could result in a robust and durable response. Along with the ability to directly kill tumor cells, NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) given the expression of Fragment Crystallizable (Fc) receptors. Promising novel antibodies modified with improved Fc-receptor-mediated functions or Fc-engagers to kill target cells have been tested in pre-clinical models with considerable results. Combination therapies with immune-therapeutic antibodies with enhancers of NK-cell Fc-receptor-mediated function can be exploited to increase the efficacy of these antibodies. Herein, I discuss possible strategies to improve the success of immunotherapy by boosting NK cell function. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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23 pages, 1207 KiB

Open AccessReview

NK Cells in the Treatment of Hematological Malignancies

by Ana P Gonzalez-Rodriguez, Mónica Villa-Álvarez, Christian Sordo-Bahamonde, Seila Lorenzo-Herrero and Segundo Gonzalez

J. Clin. Med. 2019, 8(10), 1557; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8101557 - 27 Sep 2019

Cited by 38 | Viewed by 11143

Abstract

Natural killer (NK) cells have the innate ability to kill cancer cells, however, tumor cells may acquire the capability of evading the immune response, thereby leading to malignancies. Restoring or potentiation of this natural antitumor activity of NK cells has become a relevant therapeutic approach in cancer and, particularly, in hematological cancers. The use of tumor-specific antibodies that promote antibody-dependent cell-mediated cytotoxicity (ADCC) through the ligation of CD16 receptor on NK cells has become standard for many hematologic malignancies. Hematopoietic stem cell transplantation is another key therapeutic strategy that harnesses the alloreactivity of NK cells against cancer cells. This strategy may be refined by adoptive transfer of NK cells that may be previously expanded, activated, or redirected (chimeric antigen receptor (CAR)-NK cells) against cancer cells. The antitumor activity of NK cells can also be boosted by cytokines or immunostimulatory drugs such as lenalidomide or pomalidomide. Finally, targeting immunosubversive mechanisms developed by hematological cancers and, in particular, using antibodies that block NK cell inhibitory receptors and checkpoint proteins are novel promising therapeutic approaches in these malignant diseases. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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17 pages, 723 KiB

Open AccessReview

NK Cell Plasticity in Cancer

by Sizhe Liu, Payal Dhar and Jennifer D. Wu

J. Clin. Med. 2019, 8(9), 1492; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091492 - 19 Sep 2019

Cited by 24 | Viewed by 4065

Abstract

Natural killer (NK) cells are critical immune components in controlling tumor growth and dissemination. Given their innate capacity to eliminate tumor cells without prior sensitization, NK-based therapies for cancer are actively pursued pre-clinically and clinically. However, recent data suggest that tumors could induce functional alterations in NK cells, polarizing them to tumor-promoting phenotypes. The potential functional plasticity of NK cells in the context of tumors could lead to undesirable outcomes of NK-cell based therapies. In this review, we will summarize to-date evidence of tumor-associated NK cell plasticity and provide our insights for future investigations and therapy development. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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17 pages, 792 KiB

Open AccessReview

NK Cells as Potential Targets for Immunotherapy in Endometriosis

by Aneta Ścieżyńska, Michał Komorowski, Marta Soszyńska and Jacek Malejczyk

J. Clin. Med. 2019, 8(9), 1468; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091468 - 14 Sep 2019

Cited by 45 | Viewed by 5400

Abstract

Endometriosis is a common gynecological disease defined by the presence of endometrial-like tissue outside the uterus, most frequently on the pelvic viscera and ovaries, which is associated with pelvic pains and infertility. It is an inflammatory disorder with some features of autoimmunity. It is accepted that ectopic endometriotic tissue originates from endometrial cells exfoliated during menstruation and disseminating into the peritoneum by retrograde menstrual blood flow. It is assumed that the survival of endometriotic cells in the peritoneal cavity may be partially due to their abrogated elimination by natural killer (NK) cells. The decrease of NK cell cytotoxic activity in endometriosis is associated with an increased expression of some inhibitory NK cell receptors. It may be also related to the expression of human leukocyte antigen G (HLA-G), a ligand for inhibitory leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) receptors. The downregulated cytotoxic activity of NK cells may be due to inhibitory cytokines present in the peritoneal milieu of patients with endometriosis. The role of NK cell receptors and their ligands in endometriosis is also confirmed by genetic association studies. Thus, endometriosis may be a subject of immunotherapy by blocking NK cell negative control checkpoints including inhibitory NK cell receptors. Immunotherapies with genetically modified NK cells also cannot be excluded. Full article

(This article belongs to the Special Issue Development and Function of Natural Killer Cells and their Importance in Immunotherapy)

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