International Journal of Molecular Sciences

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3 pages, 172 KiB

Open AccessEditorial

Natural Killer Cells and Immunotherapy

by Ji-Yoon Noh and Haiyoung Jung

Int. J. Mol. Sci. 2023, 24(10), 8760; https://doi.org/10.3390/ijms24108760 - 15 May 2023

Cited by 2 | Viewed by 1818

Abstract

Natural killer (NK) cells are innate immune cells that demonstrate cytolytic activity against tumor cells, virus-infected cells and other physiologically stressed cells, such as senescent cells [...] Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

Research

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18 pages, 4442 KiB

Open AccessArticle

Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell–Trophoblast Interactions

by Valentina Mikhailova, Polina Grebenkina, Evgeniia Khokhlova, Alina Davydova, Zeina Salloum, Elizaveta Tyshchuk, Valeria Zagainova, Kseniia Markova, Igor Kogan, Sergey Selkov and Dmitry Sokolov

Int. J. Mol. Sci. 2022, 23(4), 2387; https://doi.org/10.3390/ijms23042387 - 21 Feb 2022

Cited by 16 | Viewed by 5115

Abstract

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their [...] Read more.

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their functional activity. An imbalance of pro- and anti-inflammatory signals can lead to the development of reproductive pathology. The aim of this study was to assess the effects of cytokines on NK cells in the presence of trophoblast cells in an in vitro model. We used TNFα, IFNγ, TGFβ and IL-10; the NK-92 cell line; and peripheral blood NK cells (pNKs) from healthy, non-pregnant women. For trophoblast cells, the JEG-3 cell line was used. In the monoculture of NK-92 cells, TNFα caused a decrease in CD56 expression. In the coculture of NK cells with JEG-3 cells, TNFα increased the expression of NKG2C and NKG2A by NK-92 cells. Under the influence of TGFβ, the expression of CD56 increased and the expression of NKp30 decreased in the monoculture. After the preliminary cultivation of NK-92 cells in the presence of TGFβ, their cytotoxicity increased. In the case of adding TGFβ to the PBMC culture, as well as coculturing PBMCs and JEG-3 cells, the expression of CD56 and NKp44 by pNK cells was reduced. The differences in the effects of TGFβ in the model using NK-92 cells and pNK cells may be associated with the possible influence of monocytes or other lymphoid cells from the mononuclear fraction. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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18 pages, 5419 KiB

Open AccessArticle

NK Cell-Dependent Antibody-Mediated Immunotherapy Is Improved In Vitro and In Vivo When Combined with Agonists for Toll-like Receptor 2 in Head and Neck Cancer Models

by Mandy Gruijs, Sonja H. Ganzevles, Marijke Stigter-van Walsum, Richard van der Mast, Monique M. van Ostaijen-ten Dam, Cornelis W. Tuk, Marco W. Schilham, C. René Leemans, Ruud H. Brakenhoff, Marjolein van Egmond, Rieneke van de Ven and Jantine E. Bakema

Int. J. Mol. Sci. 2021, 22(20), 11057; https://doi.org/10.3390/ijms222011057 - 14 Oct 2021

Cited by 6 | Viewed by 3642

Abstract

The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor [...] Read more.

The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor elimination and improving patient survival. Here, we demonstrate that cetuximab treatment combined with immunostimulatory agonists for Toll-like receptor (TLR) 2 induces profound immune responses. Natural killer (NK) cells, isolated from healthy individuals or patients with head and neck cancer, harbored enhanced cytotoxic capacity and increased tumor-killing potential in vitro. Additionally, combination treatment increased the release of several pro-inflammatory cytokines and chemokines by NK cells. Tumor-bearing mice that received cetuximab and the TLR2 ligand Pam3CSK4 showed increased infiltration of immune cells into the tumors compared to mice that received cetuximab monotherapy, resulting in a significant delay in tumor growth or even complete tumor regression. Moreover, combination treatment resulted in improved overall survival in vivo. In conclusion, combining tumor-targeting antibody-based immunotherapy with TLR stimulation represents a promising treatment strategy to improve the clinical outcomes of cancer patients. This treatment could well be applied together with other therapeutic strategies such as anti-PD-(L)1 checkpoint inhibition to further overcome immunosuppression. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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11 pages, 939 KiB

Open AccessCommunication

A Chimeric IL-15/IL-15Rα Molecule Expressed on NFκB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells

by Naomi C. Bosch, Lena-Marie Martin, Caroline J. Voskens, Carola Berking, Barbara Seliger, Gerold Schuler, Niels Schaft and Jan Dörrie

Int. J. Mol. Sci. 2021, 22(19), 10227; https://doi.org/10.3390/ijms221910227 - 23 Sep 2021

Cited by 7 | Viewed by 2925

Abstract

Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might [...] Read more.

Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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15 pages, 2513 KiB

Open AccessArticle

Ex Vivo Expanded and Activated Natural Killer Cells Prolong the Overall Survival of Mice with Glioblastoma-like Cell-Derived Tumors

by Yoichi Shida, Tsutomu Nakazawa, Ryosuke Matsuda, Takayuki Morimoto, Fumihiko Nishimura, Mitsutoshi Nakamura, Ryosuke Maeoka, Shuichi Yamada, Ichiro Nakagawa, Young-Soo Park, Motoaki Yasukawa, Takashi Tojo, Takahiro Tsujimura and Hiroyuki Nakase

Int. J. Mol. Sci. 2021, 22(18), 9975; https://doi.org/10.3390/ijms22189975 - 15 Sep 2021

Cited by 11 | Viewed by 3999

Abstract

Glioblastoma (GBM) is the leading malignant intracranial tumor and is associated with a poor prognosis. Highly purified, activated natural killer (NK) cells, designated as genuine induced NK cells (GiNKs), represent a promising immunotherapy for GBM. We evaluated the anti-tumor effect of GiNKs in [...] Read more.

Glioblastoma (GBM) is the leading malignant intracranial tumor and is associated with a poor prognosis. Highly purified, activated natural killer (NK) cells, designated as genuine induced NK cells (GiNKs), represent a promising immunotherapy for GBM. We evaluated the anti-tumor effect of GiNKs in association with the programmed death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint pathway. We determined the level of PD-1 expression, a receptor known to down-regulate the immune response against malignancy, on GiNKs. PD-L1 expression on glioma cell lines (GBM-like cell line U87MG, and GBM cell line T98G) was also determined. To evaluate the anti-tumor activity of GiNKs in vivo, we used a xenograft model of subcutaneously implanted U87MG cells in immunocompromised NOG mice. The GiNKs expressed very low levels of PD-1. Although PD-L1 was expressed on U87MG and T98G cells, the expression levels were highly variable. Our xenograft model revealed that the retro-orbital administration of GiNKs and interleukin-2 (IL-2) prolonged the survival of NOG mice bearing subcutaneous U87MG-derived tumors. PD-1 blocking antibodies did not have an additive effect with GiNKs for prolonging survival. GiNKs may represent a promising cell-based immunotherapy for patients with GBM and are minimally affected by the PD-1/PD-L1 immune evasion axis in GBM. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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13 pages, 4360 KiB

Open AccessArticle

NLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B

by Hwan Hee Lee, Dongoh Kim, Joohee Jung, Hyojeung Kang and Hyosun Cho

Int. J. Mol. Sci. 2021, 22(17), 9285; https://doi.org/10.3390/ijms22179285 - 27 Aug 2021

Cited by 27 | Viewed by 3370

Abstract

Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays [...] Read more.

Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays an important role in the innate immune response, but emerging evidence has indicated that the NLRP3 inflammasome is implicated in all stages of cancer development. Various cells express NLRP3 protein through the autocrine or paracrine signaling in their environment, but NK cells do not. The expanding evidence shows that patients who suffer from liver cancers have a low frequency of natural killer (NK) cells, and the function of these cells is also impaired. Thus, we examined how the expression of NLRP3 in HCC cells affects cancer surveillance by NK cells in a state of a co-culture of both cells. When the expression of NLRP3 in HCC cells was ablated, MICA/B on the surface of HCC cells was upregulated through the lowered expression of matrix metalloproteinase. The expression of MICA on the surface of HCC cells interacted with the NKG2D receptor on NK-92 cells, which led to NK cytotoxicity. Furthermore, in a xenograft mice model, NLRP3 KO HCC cells delayed tumor development and metastasis as well as increased the sensitivity to NK cell cytotoxicity. Taken together, NLRP3 KO in HCC could enhance NK immunosurveillance through an interaction of NKG2D-MICA. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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Review

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19 pages, 930 KiB

Open AccessReview

The iNKT Cell–Macrophage Axis in Homeostasis and Disease

by Mariana S. Cruz, José Pedro Loureiro, Maria J. Oliveira and Maria Fatima Macedo

Int. J. Mol. Sci. 2022, 23(3), 1640; https://doi.org/10.3390/ijms23031640 - 31 Jan 2022

Cited by 15 | Viewed by 5168

Abstract

Invariant natural killer T (iNKT) cells are CD1d-restricted, lipid-reactive T cells that exhibit preponderant immunomodulatory properties. The ultimate protective or deleterious functions displayed by iNKT cells in tissues are known to be partially shaped by the interactions they establish with other immune cells. [...] Read more.

Invariant natural killer T (iNKT) cells are CD1d-restricted, lipid-reactive T cells that exhibit preponderant immunomodulatory properties. The ultimate protective or deleterious functions displayed by iNKT cells in tissues are known to be partially shaped by the interactions they establish with other immune cells. In particular, the iNKT cell–macrophage crosstalk has gained growing interest over the past two decades. Accumulating evidence has highlighted that this immune axis plays central roles not only in maintaining homeostasis but also during the development of several pathologies. Hence, this review summarizes the reported features of the iNKT cell–macrophage axis in health and disease. We discuss the pathophysiological significance of this interplay and provide an overview of how both cells communicate with each other to regulate disease onset and progression in the context of infection, obesity, sterile inflammation, cancer and autoimmunity. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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28 pages, 1136 KiB

Open AccessReview

The Biological Role and Therapeutic Potential of NK Cells in Hematological and Solid Tumors

by Rodion A. Velichinskii, Maria A. Streltsova, Sofya A. Kust, Alexander M. Sapozhnikov and Elena I. Kovalenko

Int. J. Mol. Sci. 2021, 22(21), 11385; https://doi.org/10.3390/ijms222111385 - 21 Oct 2021

Cited by 14 | Viewed by 3987

Abstract

NK cells are an attractive target for cancer immunotherapy due to their potent antitumor activity. The main advantage of using NK cells as cytotoxic effectors over T cells is a reduced risk of graft versus host disease. At present, several variants of NK-cell-based [...] Read more.

NK cells are an attractive target for cancer immunotherapy due to their potent antitumor activity. The main advantage of using NK cells as cytotoxic effectors over T cells is a reduced risk of graft versus host disease. At present, several variants of NK-cell-based therapies are undergoing clinical trials and show considerable effectiveness for hematological tumors. In these types of cancers, the immune cells themselves often undergo malignant transformation, which determines the features of the disease. In contrast, the current use of NK cells as therapeutic agents for the treatment of solid tumors is much less promising. Most studies are at the stage of preclinical investigation, but few progress to clinical trials. Low efficiency of NK cell migration and functional activity in the tumor environment are currently considered the major barriers to NK cell anti-tumor therapies. Various therapeutic combinations, genetic engineering methods, alternative sources for obtaining NK cells, and other techniques are aiming at the development of promising NK cell anticancer therapies, regardless of tumorigenesis. In this review, we compare the role of NK cells in the pathogenesis of hematological and solid tumors and discuss current prospects of NK-cell-based therapy for hematological and solid tumors. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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32 pages, 1347 KiB

Open AccessReview

Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery

by Marisa Market, Gayashan Tennakoon and Rebecca C. Auer

Int. J. Mol. Sci. 2021, 22(21), 11378; https://doi.org/10.3390/ijms222111378 - 21 Oct 2021

Cited by 25 | Viewed by 5034

Abstract

Surgical resection is the foundation for the curative treatment of solid tumors. However, metastatic recurrence due to the difficulty in eradicating micrometastases remain a feared outcome. Paradoxically, despite the beneficial effects of surgical removal of the primary tumor, the physiological stress resulting from [...] Read more.

Surgical resection is the foundation for the curative treatment of solid tumors. However, metastatic recurrence due to the difficulty in eradicating micrometastases remain a feared outcome. Paradoxically, despite the beneficial effects of surgical removal of the primary tumor, the physiological stress resulting from surgical trauma serves to promote cancer recurrence and metastasis. The postoperative environment suppresses critical anti-tumor immune effector cells, including Natural Killer (NK) cells. The literature suggests that NK cells are critical mediators in the formation of metastases immediately following surgery. The following review will highlight the mechanisms that promote the formation of micrometastases by directly or indirectly inducing NK cell suppression following surgery. These include tissue hypoxia, neuroendocrine activation, hypercoagulation, the pro-inflammatory phase, and the anti-inflammatory phase. Perioperative therapeutic strategies designed to prevent or reverse NK cell dysfunction will also be examined for their potential to improve cancer outcomes by preventing surgery-induced metastases. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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