scholarly journals Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

scholarly journals Enhanced adaptive immune responses in lung adenocarcinoma through natural killer cell stimulation

2019 ◽  
Vol 116 (35) ◽  
pp. 17460-17469 ◽  
Author(s):  
Leah Schmidt ◽  
Banu Eskiocak ◽  
Ryan Kohn ◽  
Celeste Dang ◽  
Nikhil S. Joshi ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Production Capacity ◽  
Dependent Manner ◽  
Cell Stimulation ◽  
Established Disease

Natural killer (NK) cells inhibit tumor development in mouse models and their presence in tumors correlates with patient survival. However, tumor-associated NK cells become dysfunctional; thus, stimulation of NK cells in cancer is emerging as an attractive immunotherapeutic strategy. In a mouse model of lung adenocarcinoma, NK cells localized to tumor stroma with immature phenotypes and low functional capacity. To test their responsiveness within established disease, we engineered a system for inducible expression of activating ligands in tumors. After stimulation, NK cells localized inside tumors, with increased cytokine production capacity. Strikingly, T cells were also recruited to tumors in an NK cell-dependent manner, and exhibited higher functionality. In neoantigen-expressing tumors, NK cell stimulation enhanced the number and function of tumor-specific T cells and, in long-term settings, reduced tumor growth. Thus, even in established disease NK cells can be activated to contribute to antitumor immunity, supporting their potential as an important target in cancer immunotherapy.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

Elevated CD54 Expression Renders CD4+ T Cells Susceptible to Natural Killer Cell-Mediated Killing

2019 ◽  
Vol 220 (12) ◽  
pp. 1892-1903 ◽  
Author(s):  
Xi Chen ◽  
Huihui Chen ◽  
Zining Zhang ◽  
Yajing Fu ◽  
Xiaoxu Han ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Adaptive Immune Response ◽  
Phenotypic Analysis

Abstract Background Natural killer (NK) cells are an important type of effector cell in the innate immune response, and also have a role in regulation of the adaptive immune response. Several studies have indicated that NK cells may influence CD4+ T cells during HIV infection. Methods In total, 51 HIV-infected individuals and 15 healthy controls participated in this study. We performed the flow cytometry assays and real-time PCR for the phenotypic analysis and the functional assays of NK cell-mediated deletion of CD4+ T cells, phosphorylation of nuclear factor-κB (NF-κB/p65) and the intervention of metformin. Results Here we detected high CD54 expression on CD4+ T cells in HIV-infected individuals, and demonstrate that upregulated CD54 is associated with disease progression in individuals infected with HIV. We also show that CD54 expression leads to the deletion of CD4+ T cells by NK cells in vitro, and that this is modulated by NF-κB/p65 signaling. Further, we demonstrate that metformin can suppress CD54 expression on CD4+ T cells by inhibiting NF-κB/p65 phosphorylation. Conclusions Our data suggest that further studies to evaluate the potential role of metformin as adjunctive therapy to reconstitute immune function in HIV-infected individuals are warranted.

scholarly journals Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2869-2877 ◽  
Author(s):  
Gillian C. Whittaker ◽  
Deborah N. Burshtyn ◽  
Selinda J. Orr ◽  
Laura Quigley ◽  
Deborah L. Hodge ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Fine Tuning ◽  
Receptor Coupling ◽  
Integral Proteins ◽  
Activation Motif

AbstractThe linker for activation of T cells (LAT) and the linker for activation of B cells (LAB/NTAL/LAT2) are integral proteins in receptor coupling to downstream events. Both proteins are expressed in natural killer (NK) cells and LAT is phosphorylated during target cell interactions or ligation of the immunoreceptor tyrosine-based activation motif (ITAM)–coupled CD16. Regardless, Lat−/− mice exhibit normal natural and antibody-mediated killing. Here we place both LAT and LAB in the DAP12 pathway of NK cells. Moreover, we unveil a LAT-independent pathway that requires expression of Syk. Mice lacking either LAT or LAB have a skewed Ly49 repertoire, and activated NK cells from Lat−/− mice have reduced responses to the ITAM-coupled receptor NK1.1. In contrast, resting Lat−/− NK cells show intact NK1.1 responses, whereas NK cells without LAB are hyperactive. Elimination of both adaptors severely reduces NK1.1 signaling under both conditions. Together these data show that NK ITAMs preferentially use a signaling cassette regulated by interplay between LAT and LAB. Activation by interleukin-2 causes a shift to greater dependency on LAT due to suppression of Syk signaling. The overlapping use of multiple adaptors permits fine-tuning of NK-cell ITAM responses over the course of an immune response.

scholarly journals Mechanical Regulation of the Cytotoxic Activity of Natural Killer Cells

2020 ◽  
Author(s):  
L. Mordechay ◽  
G. Le Saux ◽  
A. Edri ◽  
U. Hadad ◽  
A. Porgador ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Activation Mechanism ◽  
Catch Bond ◽  
Immune Activity ◽  
The Third

AbstractMechanosensing has been recently explored for T cells and B cells and is believed to be part of their activation mechanism. Here, we explore the mechanosensing of the third type of lymphocytes – Natural Killer (NK) cells, by showing that they modulate their immune activity in response to changes in the stiffness of a stimulating surface. Interestingly, we found that this immune response is bell-shaped, and peaks for a stiffness of a few hundreds of kPa. This bell-shape behavior was observed only for surfaces functionalized with the activating ligand MHC class I polypeptide-related sequence A (MICA), but not for control surfaces lacking immunoactive functionalities. We found that stiffness does not affect uniformly all cells but increases the size of a little group of extra-active cells, which in turn contribute to the overall activation effect of the entire cell population. We further imaged the clustering of costimulatory adapter protein DAP10 on NK cell membrane and found that it shows the same bell –shape dependence to surface stiffness. Based on these findings, we propose a catch-bond-based model for the mechanoregulation of NK cell cytotoxic activity, through interaction of NKG2D activating receptors with MICA. Our findings reveal what seems to be “the tip of iceberg” of mechanosensation of NK cells, and provides an important insight on the mechanism of their immune signaling.Statement of SignificanceThe mechanical sensing of immune lymphocytes was recently demonstrated for T cells and B cells, but not for the third type of lymphocytes – Natural Killer (NK) cells. Interestingly, previous reports on lymphocyte mechanosensing were controversial, and showed either positive or negative changes in their immune activity with environmental stiffness, depending on the stiffness range. In this paper, we directly demonstrated that NK cells modulate their response with the stiffness of the stimulating surface, and this modulation has a bell-shape trend. We found that there is a strong correlation between the response to stiffness and clustering of adaptor proteins. Upon this correlation, we proposed a mechanosensing model based on the catch-bond nature of activating ligand-receptor complexes in NK cells.

scholarly journals TXNIP Regulates Natural Killer Cell-Mediated Innate Immunity by Inhibiting IFN-γ Production during Bacterial Infection

2020 ◽  
Vol 21 (24) ◽  
pp. 9499
Author(s):  
Dong Oh Kim ◽  
Jae-Eun Byun ◽  
Won Sam Kim ◽  
Mi Jeong Kim ◽  
Jung Ha Choi ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Transforming Growth Factor Β ◽  
Primary Mouse ◽  
Ifn Γ

The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip−/− (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.

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

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3567-3574 ◽  
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.

A role for Blimp1 in the transcriptional network controlling natural killer cell maturation

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1869-1879 ◽  
Author(s):  
Axel Kallies ◽  
Sebastian Carotta ◽  
Nicholas D. Huntington ◽  
Nicholas J. Bernard ◽  
David M. Tarlinton ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cytokine Production ◽  
Plasma Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
B Cell Lymphoma ◽  
Cell Maturation ◽  
Proliferative Potential

Abstract Natural killer (NK) cells are innate lymphocytes capable of immediate effector functions including cytokine production and cytotoxicity. Compared with B and T cells, the factors that control the peripheral maturation of NK cells are poorly understood. We show that Blimp1, a transcriptional repressor required for the differentiation of plasma cells and short-lived effector T cells, is expressed by NK cells throughout their development. Interleukin 15 (IL-15) is required for the early induction of Blimp1 in NK cells, with expression increasing in the most mature subsets of mouse and human NK cells. We show that Blimp1 is required for NK-cell maturation and homeostasis and for regulating their proliferative potential. It is also essential for high granzyme B expression, but not for most cytokine production and cytotoxicity. Surprisingly, interferon regulatory factor 4 (IRF4) and B-cell lymphoma 6 (Bcl6), 2 transcription factors crucial for the regulation of Blimp1 in B and T cells, are largely dispensable for Blimp1 expression in NK cells. T-bet deficiency, however, leads to attenuated Blimp1 expression. We have identified NK cells as the first hematopoietic cell type in which the IRF4-Blimp1-Bcl6 regulatory axis is not in operation, highlighting the distinct nature of the NK-cell gene-regulatory network.

scholarly journals Critical role for the Ly49 family of class I MHC receptors in adaptive natural killer cell responses

2018 ◽  
Vol 115 (45) ◽  
pp. 11579-11584 ◽  
Author(s):  
Andrew Wight ◽  
Ahmad Bakur Mahmoud ◽  
Michal Scur ◽  
Megan M. Tu ◽  
Mir Munir A. Rahim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Class I ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Class I Mhc ◽  
Memory Response

Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen-specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell.

scholarly journals Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer

2018 ◽  
Vol 115 (46) ◽  
pp. 11808-11813 ◽  
Author(s):  
Lei Shi ◽  
Kang Li ◽  
Yizhan Guo ◽  
Anirban Banerjee ◽  
Qing Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Surface Expression ◽  
Intrinsic Factors ◽  
Immunologic Control

Natural killer (NK) cells play a critical role in controlling malignancies. Susceptibility or resistance to lung cancer, for example, specifically depends on NK cell function. Nevertheless, intrinsic factors that control NK cell-mediated clearance of lung cancer are unknown. Here we report that NK cells exposed to exogenous major histocompatibility class I (MHCI) provide a significant immunologic barrier to the growth and progression of malignancy. Clearance of lung cancer is facilitated by up-regulation of NKG2D, NKp46, and other activating receptors upon exposure to environmental MHCI. Surface expression of the inhibitory receptor Ly49C/I, on the other hand, is down-regulated upon exposure to tumor-bearing tissue. We thus demonstrate that NK cells exhibit dynamic plasticity in surface expression of both activating and inhibitory receptors based on the environmental context. Our data suggest that altering the activation state of NK cells may contribute to immunologic control of lung and possibly other cancers.

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