Special Issue "Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 15 January 2020.

Special Issue Editor

Prof. Dr. Anahid Jewett
E-Mail Website
Guest Editor
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Jonsson Comprehensive Cancer Center, School of Dentistry, University of California-Los Angeles, CHS, B3-088, 10833 LeConte Ave., Los Angeles, CA 90095, USA
Interests: natural killer cells; differentiation; cancer stem cells/poorly differentiated tumors

Special Issue Information

Dear Colleagues,

Renewed interest in adoptive NK cell therapy has generated quite a lot of enthusiasm among NK cell biologists in recent years. The demonstration of the ability of NK cells to target cancer stem cells and poorly differentiated tumors that lack or express very low levels of MHC class I has afforded these cells a very unique and indispensable role in cancer immunotherapy. It is also known that cancer patients have significantly suppressed NK cell numbers and function, and indeed, inactivation of NK function has been shown to occur at the pre-neoplastic stages of tumorigenesis, making these cells as one of the most important immune effectors responsible for the curtailment or inhibition of cancer.

However, limitation in the expansion of NK cells to sufficient numbers for clinical use, inability to obtain functional NK cells from different cellular sources, and lack of adequate understanding of the immunobiology of these cells have traditionally hampered the progress in the field of NK cell Immunotherapy. NK and T cells have to operate within a very complex and immunosuppressive tumor microenvironment. To this end, tumor infiltrating fat cells and fibroblasts which constitute important components of stromal cells in addition to MDSCs and Tregs may not only shape the numbers and function of NK cells but also other immune effectors such as CD8+ T cells. Indeed, recent work from our laboratory indicates that obesity in combination with genetic alterations in the pancreas is a driving force for NK cell immunosuppression at the pre-neoplastic stage of tumorigenesis.

Therefore, strategies should be designed to allow maintenance of good NK expansion and function in cancer patients, since NK cells are known to limit the expansion of tumor-associated macrophages (TAMs), Tregs, and MDSCs and result in the removal of CSCs/undifferentiated tumors, all of which are the hallmarks of aggressive tumors. Large numbers of functionally competent NK cells can be combined with other immunotherapeutic strategies, such as oncolytic viruses, ADCC-inducing antibodies, check point inhibitors, CAR-T, CAR-NK, TIL, and chemotherapeutic and radiotherapeutic strategies for the ultimate goal of tumor eradication.

This collection of reviews and original articles presented in this volume highlights the significant advances made in the field of NK cells and potential new directions which should help to advance the field and bring us to the finish line. After all, we should not forget that the beneficiaries are all those who have valiantly fought against cancer and are looking up to the scientific community for treatments that are not only effective in curing their cancer but also allowing them to enjoy a good quality of life.

Prof. Dr. Anahid Jewett
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 papers will be 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. Cancers 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 1800 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.


  • NK cells
  • NK-CAR
  • Differentiation
  • Cancer stem cells
  • NK immunotherapy

Published Papers (2 papers)

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Open AccessReview
Exosomes: Versatile Nano Mediators of Immune Regulation
Cancers 2019, 11(10), 1557; https://doi.org/10.3390/cancers11101557 - 14 Oct 2019
One of many types of extracellular vesicles (EVs), exosomes are nanovesicle structures that are released by almost all living cells that can perform a wide range of critical biological functions. Exosomes play important roles in both normal and pathological conditions by regulating cell-cell [...] Read more.
One of many types of extracellular vesicles (EVs), exosomes are nanovesicle structures that are released by almost all living cells that can perform a wide range of critical biological functions. Exosomes play important roles in both normal and pathological conditions by regulating cell-cell communication in cancer, angiogenesis, cellular differentiation, osteogenesis, and inflammation. Exosomes are stable in vivo and they can regulate biological processes by transferring lipids, proteins, nucleic acids, and even entire signaling pathways through the circulation to cells at distal sites. Recent advances in the identification, production, and purification of exosomes have created opportunities to exploit these structures as novel drug delivery systems, modulators of cell signaling, mediators of antigen presentation, as well as biological targeting agents and diagnostic tools in cancer therapy. This review will examine the functions of immunocyte-derived exosomes and their roles in the immune response under physiological and pathological conditions. The use of immunocyte exosomes in immunotherapy and vaccine development is discussed. Full article
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Open AccessReview
Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors
Cancers 2019, 11(10), 1534; https://doi.org/10.3390/cancers11101534 - 11 Oct 2019
In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating [...] Read more.
In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors. Full article

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Killer signaling of natural tumor recognition

Lizeth G. Meza Guzman1,2 and Sandra E. Nicholson1,2

1 The Walter and Eliza Hall Institute of Medical Research. Parkville, Victoria, Australia,

2 Department of Medical Biology, The University of Melbourne, Victoria, Australia

Natural killer (NK) cells play a pivotal role in cancer-immunotherapy due to their innate ability to target and kill tumorigenic cells. NK cells engage and kill tumour cells by expressing a myriad of activating and inhibitory receptors. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, which is regulated through a fine balance of the signalling cascades downstream of the activating and inhibitory receptors. Although a cytotoxic response is favourable when engaging tumour cells, tumour cells can modulate the surface expression of receptor ligands in order to escape the immune system. Additionally, harsh conditions in the tumour microenvironment (TME) tilt the scales towards a suppressed cytotoxic NK response. In order to fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance within the TME. This review will focus on the intracellular signalling pathways activated or suppressed in NK cells within the TME and the roles the signalling intermediates play during an NK cytotoxic response.

Ovarian clear cell carcinoma is defectively recognized by autologous NK cells
Silvia Parolini, Giovanna Tabellini

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

In the present study, we report natural killer (NK) cell analysis derived from patients affected by rare ovarian cancer histotype of clear cell carcinoma (OCCC). We analyzed the phenoype of NK cells derived from peripheral bloods (PB) and peritoneal fluids (PF) and valuated on the first cytotoxic interaction between NK cells and autologous primary tumor cells derived from patients.We performed multiparametric cytofluorimetric analysis of NK cells and autologous tumor cells derived from six patients. We valuated cytotoxic capability, by degranulation assay, of patient NK cells against autologous clear cell carcinoma cells. We provide evidence of altered degranulation ability of NK cells derived from peritoneal fluid of patients /versus /autologous tumor cells. Moreover we also analyzed tumor cell ligands recognized by NK cell activating receptors and we show that patient NK cells were not able to recognize autologous tumor cells. So we think that this severe defect of lysis could be due to defective expression of NK cell receptor ligands stimulating various activating receptors. In the present study, for the first time, the phenotypic and functional properties of tumor associated NK cells derived from PF of six patients with advanced stage of OCCC are analyzed. These described altered interaction between NK cells and ATC lines begin to shed light on this particularly aggressive mechanisms of this histopyte tumor and will be fundamental expand the cases for more effective therapies.

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