Immune Circuits to Shape Natural Killer Cells in Cancer

Natural killer (NK) cells are innate lymphoid cells playing an important role in anti-cancer immunity. NK cells are efficient in controlling the spreading of metastasis but are not very powerful in fighting against primary tumors. The NK cell capability to infiltrate and persist in the tumor microenvironment and to exert their antitumoral functions is often limited by tumor escape mechanisms. These tumor-mediated strategies not only induce NK cell tolerance but also interfere with the NK cell-dependent immune networking. This review will provide an overview of the tumor escape mechanisms impacting NK cells, identify the immune circuits regulating the NK cell-dependent antitumor immunity and revise the emerging therapeutic approaches to unleash NK cells in cancer.

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Polysaccharide from Codium fragile Induces Anti-Cancer Immunity by Activating Natural Killer Cells

Marine Drugs ◽

10.3390/md18120626 ◽

2020 ◽

Vol 18 (12) ◽

pp. 626

Author(s):

Hae-Bin Park ◽

Juyoung Hwang ◽

Wei Zhang ◽

Seulgi Go ◽

Jihoe Kim ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Nk Cell ◽

The Body ◽

Cell Infiltration ◽

Codium Fragile ◽

Cancer Immunity ◽

Anti Cancer ◽

Ifn Γ

Natural polysaccharides exhibit beneficial immune modulatory effects, including immune stimulatory and anti-cancer activities. In this study, we examined the effect of Codium fragile polysaccharide (CFP) on natural killer (NK) cell activation, and its effect on tumor-bearing mice. Intravenous CFP treatment of C57BL/6 mice resulted in the upregulation of CD69, which is a marker associated with NK cell activation. In addition, intracellular levels of interferon (IFN)-γ and the cytotoxic mediators perforin and granzyme B were markedly increased in response to the CFP treatment of splenic NK cells. IFN-γ production by NK cells was directly induced by CFP, whereas the upregulation of CD69 and cytotoxic mediators required IL-12. Finally, intraperitoneal treatment with CFP prevented CT-26 (murine carcinoma) tumor cell infiltration in the lungs, without significantly reducing the body weight. In addition, treatment with CFP prevented B16 melanoma cell infiltration in the lung of C57BL/6 mice. Moreover, the anti-tumor effect was diminished by the depletion of NK cells. Therefore, these data suggest that CFP may be used as an NK cell stimulator to produce a phenomenon that contributes to anti-cancer immunity.

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The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

Frontiers in Immunology ◽

10.3389/fimmu.2020.621254 ◽

2021 ◽

Vol 11 ◽

Author(s):

Erin E. Peterson ◽

Kevin C. Barry

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Cross Talk ◽

Immune Cell ◽

Nk Cell ◽

Cell Axis ◽

Cancer Immunity ◽

Anti Cancer ◽

Patient Responses

Natural killer (NK) cells and dendritic cells (DCs) are crucial mediators of productive immune responses to infection and disease. NK cells and a subtype of DCs, the type 1 conventional DCs (cDC1s), are individually important for regulating immune responses to cancer in mice and humans. Recent work has found that NK cells and cDC1s engage in intercellular cross-talk integral to initiating and coordinating adaptive immunity to cancer. This NK cell–cDC1 axis has been linked to increased overall survival and responses to anti-PD-1 immunotherapy in metastatic melanoma patients. Here, we review recent findings on the role of NK cells and cDC1s in protective immune responses to cancer and immunotherapy, as well as current therapies targeting this NK cell–cDC1 axis. Further, we explore the concept that intercellular cross-talk between NK cells and cDC1s may be key for many of the positive prognostic associations seen with NK cells and DCs individually. It is clear that increasing our understanding of the NK cell–cDC1 innate immune cell axis will be critical for the generation of novel therapies that can modulate anti-cancer immunity and increase patient responses to common immunotherapies.

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Immunosenescence of Natural Killer Cells, Inflammation, and Alzheimer’s Disease

International Journal of Alzheimer s Disease ◽

10.1155/2018/3128758 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Corona Solana ◽

Raquel Tarazona ◽

Rafael Solana

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Lymphoid Cells ◽

Target Cells ◽

The Brain

Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (Aβ). Although Aβ have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes. The production of proinflammatory cytokines and other inflammatory mediators such as prostaglandins and complement factors favours the recruitment of peripheral immune cells further promoting neuroinflammation. Age-related inflammation and chronic infection with herpes virus such as cytomegalovirus may also contribute to inflammation in AD patients. Natural killer (NK) cells are innate lymphoid cells involved in host defence against viral infections and tumours. Once activated NK cells secrete cytokines such as IFN-γ and TNF-α and chemokines and exert cytotoxic activity against target cells. In the elderly, changes in NK cell compartment have been described which may contribute to the lower capacity of elderly individuals to respond to pathogens and tumours. Recently, the role of NK cells in the immunopathogenesis of AD is discussed. Although in AD patients the frequency of NK cells is not affected, a high NK cell response to cytokines has been described together with NK cell dysregulation of signalling pathways which is in part involved in this altered behaviour.

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Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00477.2017 ◽

2018 ◽

Vol 315 (6) ◽

pp. L977-L990 ◽

Cited By ~ 6

Author(s):

Matthew T. Rätsep ◽

Stephen D. Moore ◽

Salema Jafri ◽

Melissa Mitchell ◽

Hugh J. M. Brady ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Nk Cells ◽

Natural Killer ◽

Mouse Models ◽

Vascular Function ◽

Nk Cell ◽

Killer Cell ◽

Systolic Pressure ◽

Left Ventricular ◽

Lymphoid Cells

Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3−/− mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.

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Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00348-8 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Yuqing Cao ◽

Xiaoyu Wang ◽

Tianqiang Jin ◽

Yu Tian ◽

Chaoliu Dai ◽

...

Keyword(s):

Nk Cells ◽

Cancer Immunotherapy ◽

Natural Killer ◽

Immune Checkpoint ◽

Therapeutic Target ◽

Nk Cell ◽

Lymphoid Cells ◽

Immune Checkpoints ◽

Immune Checkpoint Molecules

Abstract Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

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Early Evaluation Of Natural Killer Cell Reconstitution Following Unmanipulated Haploidentical Transplantation Compared With HLA-Identical Sibling Transplantation

Blood ◽

10.1182/blood.v122.21.5480.5480 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5480-5480

Author(s):

Isabel Gonzalez-Gascon y Marin ◽

Ana María Pérez-Corral ◽

Jorge Gayoso ◽

Javier Anguita ◽

Ana Carolina Franco ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cyclosporine A ◽

Peripheral Blood ◽

Nk Cell ◽

Lymphoid Cells ◽

High Dose ◽

Color Flow ◽

Activating Receptors ◽

Activating Receptor

Abstract Background The main functions of Natural Killer (NK) cells are early protection against viruses or tumour cells and production of cytokines that regulate immune functions. NK cells are the first lymphoid cells to repopulate the marrow after Stem Cell Transplantation (SCT) and reach normal levels within 1 month after transplant. Acquisition of both, inhibiting and activating receptors on developing NK cells is an important step in their functional maturation. Previous studies showed the beneficial effect of NK alloreactivity in prevention of relapse, especially in the setting of haploidentical SCT. The aim of this study is to compare the reconstitution of the NK cell compartment during the first 3 months after unmanipulated haploidentical peripheral blood SCT (Haplo) and HLA-identical sibling peripheral blood SCT (HLA-id). Patients and Methods 11 adult patients received SCT (7 Haplo and 4 HLA-id) at Gregorio Marañón Hospital (Madrid-Spain) from November 2012 to April 2013. Conditioning regimen comprised fludarabine, cyclophosphamide and busulfan for Haplo SCT and fludarabine and busulfan or fludaribine and melphalan for HLA-id SCT. Prophylaxis for acute graft-versus-host disease consisted of high dose cyclophosphamide on days +3 and +4, cyclosporine A and mycophenolate mofetil for Haplo and Cyclosporine A and methotrexate for HLA-id. Patient´s characteristics and transplant outcomes are shown in table 1. We analysed reconstitution patterns and phenotype of NK at day +15, +30, +60, and +90 after transplantation by multi-color flow cytometry on FC500 Beckman Coulter® cytometer using the following anti-human monoclonal antibodies: CD3 FITC, CD56 ECD, CD45 PC7, NKG2A PC7, NKp30 PC5, NKp44 PE, Nkp46 PC5, and NKG2D PE (Beckman Coulter®). For comparison between the two groups Mann–Whitney U-test was used. Results 2/7 patients who received Haplo SCT died early in the post-transplantation period (day +50 and +66), and were excluded of the analysis because NK cells were not recovered by those days. NK cells reached normal levels by day +30: median 71 cells/µl (21-1089)) after Haplo; median 213.5 cells/µl (113-499) after HLA-id, and remained at high levels through follow up, with no significant differences between the two groups. Similarly to previous studies, a large percentage of NKbright cells was observed at day +30 after Haplo (median 89% of NK cells (55-97%)), a percentage that tended to decrease at day +60 (30% (7-38%)) and +90 (35% (10-45%)). Interestingly the percentage of NKbright cells after HLA-id SCT at day +30 (median 14.5% of NK cells (6-30%)) compared with Haplo, was significantly lower (p=0.016). This was accompanied by a significantly lower expression of inhibitory receptor NKG2A after HLA-id SCT than after Haplo: 59.5% (50-62%) versus 92.5% (50-62%) at day +30; 54% (38-61%) versus 86% (70-88%) versus at day +60 (p=0.016). Activating receptors NKp44 and NKp30 showed a low expression after both types of SCT throughout the first 3 months after transplantation. By contrast, activating receptor NKp46 levels were significantly higher at day +30 after Haplo than after HLA-id SCT (93% (87-98%) versus 50% (37-51%)) (p=0.016). Finally, high and similar proportions of activating receptor NKG2D were observed in both types of SCT. Figure 1 illustrates the recovery of the NK cell receptor phenotype for each type of SCT. Conclusions Our data showed an early and fast recovery of NK cells after Haplo and HLA-id SCT. However, phenotypic maturation of NK cells appears to be different for each type of transplant. NK cells generated after Haplo exhibit a more immature phenotype, characterized by a higher proportion of NKbright cells, and a higher expression of NKG2A at day +30. Interestingly expression of NKp46 was significantly higher after Haplo than after HLA-id SCT. Other authors have reported cytotoxic activity of these NK cells with high expression of NKp46, suggesting that cytotoxicity may be preserved in these immature NK cells. NKp30, NKG2D and NKp44 expression is less affected by the type of SCT. Acknowledgments This work has been partially supported by Project “Evaluación de la reconstitución inmune después del trasplante haploidéntico de progenitores hemopoyéticos sin depleción T” from Fundación Mutua Madrileña. Disclosures: No relevant conflicts of interest to declare.

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Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s

10.1101/642017 ◽

2019 ◽

Author(s):

Eugene Park ◽

Swapneel J. Patel ◽

Qiuling Wang ◽

Prabhakar S. Andhey ◽

Konstantin Zaitsev ◽

...

Keyword(s):

Steady State ◽

Tumor Microenvironment ◽

Toxoplasma Gondii ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Cell Conversion ◽

Ongoing Infection

AbstractInnate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describeToxoplasma gondiiinfection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes−Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

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Pseudomonas aeruginosa Infection Impairs NKG2D-Dependent NK Cell Cytotoxicity through Regulatory T-Cell Activation

Infection and Immunity ◽

10.1128/iai.00363-20 ◽

2020 ◽

Vol 88 (12) ◽

Author(s):

Mickael Vourc’h ◽

Gaelle David ◽

Benjamin Gaborit ◽

Alexis Broquet ◽

Cedric Jacqueline ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Nk Cells ◽

Natural Killer ◽

Antitumor Immunity ◽

Nk Cell ◽

Dependent Manner ◽

Cell Cytotoxicity ◽

Content Type ◽

Cytotoxic Response ◽

Nk Cell Cytotoxicity

ABSTRACT Natural killer (NK) cells play a key role in both antibacterial and antitumor immunity. Pseudomonas aeruginosa infection has already been reported to alter NK cell functions. We studied in vitro the effect of P. aeruginosa on NK cell cytotoxic response (CD107a membrane expression) to a lymphoma cell line. Through positive and negative cell sorting and adoptive transfer, we determined the influence of monocytes, lymphocytes, and regulatory T cells (Treg) on NK cell function during P. aeruginosa infection. We also studied the role of the activating receptor natural killer group 2D (NKG2D) in NK cell response to B221. We determined that P. aeruginosa significantly altered both cytotoxic response to B221 and NKG2D expression on NK cells in a Treg-dependent manner and that the NKG2D receptor was involved in NK cell cytotoxic response to B221. Our results also suggested that during P. aeruginosa infection, monocytes participated in Treg-mediated NK cell alteration. In conclusion, P. aeruginosa infection impairs NK cell cytotoxicity and alters antitumor immunity. These results highlight the strong interaction between bacterial infection and immunity against cancer.

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Contributions of natural killer cells to the immune response against Plasmodium

Malaria Journal ◽

10.1186/s12936-019-2953-1 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 9

Author(s):

Kristina S. Burrack ◽

Geoffrey T. Hart ◽

Sara E. Hamilton

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cell Function ◽

Nk Cell ◽

Lymphoid Cells ◽

Type I ◽

Experimental Cerebral Malaria ◽

Effector Cells ◽

Intracellular Parasites ◽

Innate Effector

Abstract Natural killer (NK) cells are important innate effector cells that are well described in their ability to kill virally-infected cells and tumors. However, there is increasing appreciation for the role of NK cells in the control of other pathogens, including intracellular parasites such as Plasmodium, the cause of malaria. NK cells may be beneficial during the early phase of Plasmodium infection—prior to the activation and expansion of antigen-specific T cells—through cooperation with myeloid cells to produce inflammatory cytokines like IFNγ. Recent work has defined how Plasmodium can activate NK cells to respond with natural cytotoxicity, and inhibit the growth of parasites via antibody-dependent cellular cytotoxicity mechanisms (ADCC). A specialized subset of adaptive NK cells that are negative for the Fc receptor γ chain have enhanced ADCC function and correlate with protection from malaria. Additionally, production of the regulatory cytokine IL-10 by NK cells prevents overt pathology and death during experimental cerebral malaria. Now that conditional NK cell mouse models have been developed, previous studies need to be reevaluated in the context of what is now known about other immune populations with similarity to NK cells (i.e., NKT cells and type I innate lymphoid cells). This brief review summarizes recent findings which support the potentially beneficial roles of NK cells during Plasmodium infection in mice and humans. Also highlighted are how the actions of NK cells can be explored using new experimental strategies, and the potential to harness NK cell function in vaccination regimens.

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CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features

Blood ◽

10.1182/blood-2005-02-0519 ◽

2005 ◽

Vol 106 (10) ◽

pp. 3567-3574 ◽

Cited By ~ 15

Author(s):

Chung-Wu Lin ◽

Ting-Yun Liu ◽

Shee-Uan Chen ◽

Kun-Teng Wang ◽

L. Jeffrey Medeiros ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Cell Lineage ◽

Lymphoid Cells ◽

Terminal Deoxynucleotidyl Transferase ◽

Gene Rearrangements

AbstractMost lymphoblastic lymphomas (LBLs) are regarded as neoplasms of immature T cells because they express cytoplasmic CD3 and frequently carry T-cell receptor (TCR) gene rearrangements. Immature natural killer (NK) and T cells, however, have a common bipotent T/NK-cell precursor in the thymus, and NK cells also express cytoplasmic CD3. Thus, some LBLs could arise from immature NK cells. Mature NK cells express 2 CD94 transcripts: 1A, induced by interleukin 15 (IL-15), and 1B constitutively. Because immature NK cells require IL-15 for development, CD94 1A transcripts could be a marker of NK-LBL. To test this hypothesis, we used laser capture microdissection to isolate IL-15 receptor α+ lymphoid cells from the thymus and showed that these cells contained CD94 1A transcripts. We then assessed for CD94 transcripts in 21 cases of LBL that were cytoplasmic CD3+, nuclear terminal deoxynucleotidyl transferase positive (TdT+), and CD56-, consistent with either the T-cell or NK-cell lineage. We found that 7 LBLs expressed CD94 1A transcripts without TCR gene rearrangements, suggesting NK-cell lineage. Patients with NK-LBL were younger than patients with T-LBL (15 years versus 33 years; P = .11) and had a better 2-year survival (100% versus 27%; P < .01). These results improve the current classification of LBL and contribute to our understanding of NK-cell differentiation.

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