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24 pages, 5921 KiB

Open AccessArticle

Natural Killer Cell Activation Receptor NKp30 Oligomerization Depends on Its N-Glycosylation

by Ondřej Skořepa, Samuel Pazicky, Barbora Kalousková, Jan Bláha, Celeste Abreu, Tomáš Ječmen, Michal Rosůlek, Alexander Fish, Arthur Sedivy, Karl Harlos, Jan Dohnálek, Tereza Skálová and Ondřej Vaněk

Cancers 2020, 12(7), 1998; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071998 - 21 Jul 2020

Cited by 12 | Viewed by 4266

Abstract

NKp30 is one of the main human natural killer (NK) cell activating receptors used in directed immunotherapy. The oligomerization of the NKp30 ligand binding domain depends on the length of the C-terminal stalk region, but our structural knowledge of NKp30 oligomerization and its [...] Read more.

NKp30 is one of the main human natural killer (NK) cell activating receptors used in directed immunotherapy. The oligomerization of the NKp30 ligand binding domain depends on the length of the C-terminal stalk region, but our structural knowledge of NKp30 oligomerization and its role in signal transduction remains limited. Moreover, ligand binding of NKp30 is affected by the presence and type of N-glycosylation. In this study, we assessed whether NKp30 oligomerization depends on its N-glycosylation. Our results show that NKp30 forms oligomers when expressed in HEK293S GnTI⁻ cell lines with simple N-glycans. However, NKp30 was detected only as monomers after enzymatic deglycosylation. Furthermore, we characterized the interaction between NKp30 and its best-studied cognate ligand, B7-H6, with respect to glycosylation and oligomerization, and we solved the crystal structure of this complex with glycosylated NKp30, revealing a new glycosylation-induced mode of NKp30 dimerization. Overall, this study provides new insights into the structural basis of NKp30 oligomerization and explains how the stalk region and glycosylation of NKp30 affect its ligand affinity. This furthers our understanding of the molecular mechanisms involved in NK cell activation, which is crucial for the successful design of novel NK cell-based targeted immunotherapeutics. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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23 pages, 4470 KiB

Open AccessArticle

Probiotic-Treated Super-Charged NK Cells Efficiently Clear Poorly Differentiated Pancreatic Tumors in Hu-BLT Mice

by Kawaljit Kaur, Anna Karolina Kozlowska, Paytsar Topchyan, Meng-Wei Ko, Nick Ohanian, Jessica Chiang, Jessica Cook, Phyu Ou Maung, So-Hyun Park, Nicholas Cacalano, Changge Fang and Anahid Jewett

Cancers 2020, 12(1), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010063 - 24 Dec 2019

Cited by 37 | Viewed by 4532

Abstract

Background and Aims: We have previously demonstrated that the stage of differentiation of tumors has profound effect on the function of NK cells, and that stem-like/poorly differentiated tumors were preferentially targeted by the NK cells. Therefore, in this study we determined the role [...] Read more.

Background and Aims: We have previously demonstrated that the stage of differentiation of tumors has profound effect on the function of NK cells, and that stem-like/poorly differentiated tumors were preferentially targeted by the NK cells. Therefore, in this study we determined the role of super-charged NK cells in immune mobilization, lysis, and differentiation of stem-like/undifferentiated tumors implanted in the pancreas of humanized-BLT (hu-BLT) mice fed with or without AJ2 probiotics. The phenotype, growth rate and metastatic potential of pancreatic tumors differentiated by the NK cells (NK-differentiated) or patient derived differentiated or stem-like/undifferentiated pancreatic tumors were investigated. Methods: Pancreatic tumor implantation was performed in NSG and hu-BLT mice. Stage of differentiation of tumors was determined using our published criteria for well-differentiated tumors exhibiting higher surface expression of MHC- class I, CD54, and PD-L1 (B7H1) and lower expression of CD44 receptors. The inverse was seen for poorly-differentiated tumors. Results: Stem-like/undifferentiated pancreatic tumors grew rapidly and formed large tumors and exhibited lower expression of above-mentioned differentiation antigens in the pancreas of NSG and hu-BLT mice. Unlike stem-like/undifferentiated tumors, NK-differentiated MP2 (MiaPaCa-2) tumors or patient-derived differentiated tumors were not able to grow or grew smaller tumors, and were unable to metastasize in NSG or hu-BLT mice, and they were susceptible to chemotherapeutic drugs. Stem-like/undifferentiated pancreatic tumors implanted in the pancreas of hu-BLT mice and injected with super-charged NK cells formed much smaller tumors, proliferated less, and exhibited differentiated phenotype. When differentiation of stem-like tumors by the NK cells was prevented by the addition of antibodies to IFN-γ and TNF-α, tumors grew rapidly and metastasized, and they remained resistant to chemotherapeutic drugs. Greater numbers of immune cells infiltrated the tumors of NK-injected and AJ2-probiotic bacteria-fed mice. Moreover, increased IFN-γ secretion in the presence of decreased IL-6 was seen in tumors resected and cultured from NK-injected and AJ2 fed mice. Tumor-induced decreases in NK cytotoxicity and IFN-γ secretion were restored/increased within PBMCs, spleen, and bone marrow when mice received NK cells and were fed with AJ2. Conclusion: NK cells prevent growth of pancreatic tumors through lysis and differentiation, thereby curtailing the growth and metastatic potential of stem-like/undifferentiated-tumors. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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Review

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33 pages, 5071 KiB

Open AccessReview

Transcriptional Regulation of Natural Killer Cell Development and Functions

by Dandan Wang and Subramaniam Malarkannan

Cancers 2020, 12(6), 1591; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061591 - 16 Jun 2020

Cited by 34 | Viewed by 7820

Abstract

Natural killer (NK) cells are the major lymphocyte subset of the innate immune system. Their ability to mediate anti-tumor cytotoxicity and produce cytokines is well-established. However, the molecular mechanisms associated with the development of human or murine NK cells are not fully understood. [...] Read more.

Natural killer (NK) cells are the major lymphocyte subset of the innate immune system. Their ability to mediate anti-tumor cytotoxicity and produce cytokines is well-established. However, the molecular mechanisms associated with the development of human or murine NK cells are not fully understood. Knowledge is being gained about the environmental cues, the receptors that sense the cues, signaling pathways, and the transcriptional programs responsible for the development of NK cells. Specifically, a complex network of transcription factors (TFs) following microenvironmental stimuli coordinate the development and maturation of NK cells. Multiple TFs are involved in the development of NK cells in a stage-specific manner. In this review, we summarize the recent advances in the understandings of TFs involved in the regulation of NK cell development, maturation, and effector function, in the aspects of their mechanisms, potential targets, and functions. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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23 pages, 1685 KiB

Open AccessReview

Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance

by Elaheh Hashemi and Subramaniam Malarkannan

Cancers 2020, 12(6), 1553; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061553 - 12 Jun 2020

Cited by 51 | Viewed by 7153

Abstract

Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual [...] Read more.

Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual dogma that NK cells are homogeneous with limited but focused immune functions. However, emerging studies reveal that NK cells are highly heterogeneous with divergent immune functions. A distinct combination of several activation and inhibitory receptors form a diverse array of NK cell subsets in both humans and mice. Importantly, one of the central factors that determine NK cell heterogeneity and their divergent functions is their tissue residency. Decades of studies provided strong support that NK cells develop in the bone marrow. However, evolving evidence supports the notion that NK cells also develop and differentiate in tissues. Here, we summarize the molecular basis, phenotypic signatures, and functions of tissue-resident NK cells and compare them with conventional NK cells. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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33 pages, 2854 KiB

Open AccessReview

Natural Killer Cells: Tumor Surveillance and Signaling

by Lizeth G. Meza Guzman, Narelle Keating and Sandra E. Nicholson

Cancers 2020, 12(4), 952; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040952 - 11 Apr 2020

Cited by 50 | Viewed by 9945

Abstract

Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell [...] Read more.

Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. 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. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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25 pages, 759 KiB

Open AccessReview

Mechanisms of Resistance to NK Cell Immunotherapy

by Christian Sordo-Bahamonde, Massimo Vitale, Seila Lorenzo-Herrero, Alejandro López-Soto and Segundo Gonzalez

Cancers 2020, 12(4), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040893 - 07 Apr 2020

Cited by 34 | Viewed by 8073

Abstract

Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK [...] Read more.

Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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23 pages, 1844 KiB

Open AccessReview

You Have Got a Fast CAR: Chimeric Antigen Receptor NK Cells in Cancer Therapy

by Aline Pfefferle and Nicholas D. Huntington

Cancers 2020, 12(3), 706; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030706 - 17 Mar 2020

Cited by 75 | Viewed by 9844

Abstract

The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating [...] Read more.

The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating them across a wide range of malignancies. However, along with the exciting potential of CAR-T therapy comes the real possibility of serious side effects. While the FDA has approved commercialized CAR-T cell therapy, challenges associated with manufacturing, costs, and related toxicities have resulted in increased attention being paid to implementing CAR technology in innate cytotoxic natural killer (NK) cells. Here, we review the current landscape of the CAR-NK field, from successful clinical implementation to outstanding challenges which remain to be addressed to deliver the full potential of this therapy to more patients. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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21 pages, 1945 KiB

Open AccessReview

Exosomes: Versatile Nano Mediators of Immune Regulation

by Qi Li, Helei Wang, Hourong Peng, Ting Huyan and Nicholas A. Cacalano

Cancers 2019, 11(10), 1557; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101557 - 14 Oct 2019

Cited by 68 | Viewed by 5155

Abstract

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

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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19 pages, 266 KiB

Open AccessReview

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors

by Sooyeon Oh, Joo-Ho Lee, KyuBum Kwack and Sang-Woon Choi

Cancers 2019, 11(10), 1534; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101534 - 11 Oct 2019

Cited by 55 | Viewed by 7734

Abstract

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

(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)

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