Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration

AbstractNatural killer (NK) cells play critical roles in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment to and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novel in vivo zebrafish and in vitro 3D culture models to demonstrate that FAP regulates NK cell migration, extravasation, and infiltration into tumors, ultimately affecting tumor cell lysis. These findings demonstrate the necessity of proteolytic migration in NK cell function, suggest novel mechanisms of action of FAP targeting drugs, and provide an entirely new way to regulate NK cell activity.Graphical Abstract

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The role of cytokine in regulation of the natural killer cell activity

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0808423j ◽

2008 ◽

Vol 136 (7-8) ◽

pp. 423-429 ◽

Cited By ~ 5

Author(s):

Vladimir Jurisic ◽

Sladjana Stojacic-Djenic ◽

Natasa Colovic ◽

Gordana Konjevic

Keyword(s):

Immune System ◽

Nk Cells ◽

Natural Killer ◽

Cell Function ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Target Cells

Natural killer (NK) cells are characterized by a CD3-CD16+ CD56+ immunophenotype and have a central role in the innate immune system. They are defined by their capacity to kill certain tumor-target cells or virus infected cells without prior sensitization or MHC-restriction. The activity of the NK cells is determined by the balance between activation and inhibitory receptor molecules expressed on the surface of NK cells. However, several cytokines and chemokines can significantly modulate their activity, inducing increase of NK cell activity. Immunomodulation mediated by NK cells is very important mechanism in tumor immunity, as well as in other immunodepressions of the immune system. In this study, we summarize the role of several cytokines, including IFN, IL-1, IL-2, IL-4, IL-7, IL-12 and IL-17, on NK cell function. The NK cells, after activation, depending on cytokine environment, can differentiate into NK1 cells that produce Th1 cytokine type (IFN-?, IL-2, IL-12) or NK2 cells that produce Th2 type cytokines, enhance exocytosis and release of previously formed molecules from NK cells (granzyme, perforin). We also describe that the release of cytokines and mediators show local or distance effects, or induce apoptosis (mostly by secreted TNF-?) after binding appropriated killer cell receptors from TNF receptor superfamily.

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IL-17 constrains natural killer cell activity by restraining IL-15–driven cell maturation via SOCS3

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904125116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17409-17418 ◽

Cited By ~ 4

Author(s):

Xuefu Wang ◽

Rui Sun ◽

Xiaolei Hao ◽

Zhe-Xiong Lian ◽

Haiming Wei ◽

...

Keyword(s):

Antiviral Activity ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Cell Maturation ◽

Dependent Manner ◽

Deficient Mice

Increasing evidence demonstrates that IL-17A promotes tumorigenesis, metastasis, and viral infection. Natural killer (NK) cells are critical for defending against tumors and infections. However, the roles and mechanisms of IL-17A in regulating NK cell activity remain elusive. Herein, our study demonstrated that IL-17A constrained NK cell antitumor and antiviral activity by restraining NK cell maturation. It was observed that the development and metastasis of tumors were suppressed in IL-17A–deficient mice in the NK cell-dependent manner. In addition, the antiviral activity of NK cells was also improved in IL-17A–deficient mice. Mechanistically, ablation of IL-17A signaling promoted generation of terminally mature CD27−CD11b+ NK cells, whereas constitutive IL-17A signaling reduced terminally mature NK cells. Parabiosis or mixed bone marrow chimeras from Il17a−/−and wild-type (WT) mice could inhibit excessive generation of terminally mature NK cells induced by IL-17A deficiency. Furthermore, IL-17A desensitized NK cell responses to IL-15 and suppressed IL-15–induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) via up-regulation of SOCS3, leading to down-regulation of Blimp-1. Therefore, IL-17A acts as the checkpoint during NK cell terminal maturation, which highlights potential interventions to defend against tumors and viral infections.

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Hemostatic Factors Contribute to Tumor Cell Metastatic Potential by a Mechanism Linked to Natural Killer Cell Function.

Blood ◽

10.1182/blood.v104.11.690.690 ◽

2004 ◽

Vol 104 (11) ◽

pp. 690-690 ◽

Cited By ~ 2

Author(s):

Joseph S. Palumbo ◽

Kathryn E. Talmage ◽

Jessica V. Massari ◽

Christine M. La Jeunesse ◽

Matthew J. Flick ◽

...

Keyword(s):

Natural Killer Cell ◽

Tumor Cell ◽

Nk Cells ◽

Natural Killer ◽

Platelet Activation ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Metastatic Potential ◽

Natural Killer Cell Function

Abstract A linkage between hemostatic system components and tumor cell metastatic potential has been well established, but the underlying mechanism(s) by which various circulating and cell-associated coagulation factors and platelets promote tumor cell dissemination remains to be fully defined. One potential mechanism by which tumor cell-associated microthrombi might enhance metastatic potential is by interfering with the cytolytic elimination of tumor cell emboli by natural killer (NK) cells. In order to explore this hypothesis, we studied tumor dissemination in mice lacking either fibrinogen or Gαq, a G protein critical for platelet activation. Comparative studies of experimental lung metastasis in control and Gαq−/− mice showed that loss of platelet activation resulted in a two-orders-of-magnitude decrease in pulmonary metastatic foci formed by either Lewis lung carcinoma or B16 melanoma. The difference in metastatic success was not the result of differences in tumor growth rate, as tumors transplanted into the dorsal subcutis of Gαq−/− and wildtype animals grew at similar rates. Rather, tumor cell fate analyses using radiolabeled tumor cells showed that the survival of tumor cells within the lung was significantly improved in mice that retained platelet activation function relative to Gαq−/− mice with a profound platelet activation defect. In order to examine the potential interplay between platelet activation and natural killer cell function, we compared pulmonary tumor cell survival in cohorts of control and Gαq−/− mice immuno-depleted of NK cells with an anti-asialo GM1 antibody. Remarkably, platelet function was no longer a determinant of metastatic potential in mice lacking NK cells. Given that fibrin(ogen) is also an established determinant of metastatic success we explored whether the influence of this key hemostatic factor on tumor cell dissemination was also mechanistically-coupled to natural killer cell function. We interbred fibrinogen-deficient mice with Gz-Ly49A transgenic mice known to have a constitutive deficit in NK cells. In those cohorts of mice with normal NK cells, we affirmed the earlier finding that fibrinogen deficiency resulted in a significant diminution in metastatic potential. However, consistent with our findings in mice with defective platelet activation, fibrinogen was found to no longer be a determinant of metastatic potential in mice lacking NK cells. These data establish another important link between innate immune surveillance and the hemostatic system. Further, it appears that at least one mechanism by which tumor cell-associated microthrombi increase metastatic potential is by restricting NK cell-mediated tumor cell elimination. Given that NK cell cytotoxicity requires direct contact with any target cell, one attractive model presently being explored is that tumor cell-associated platelets physically block NK cell access to tumor cell emboli.

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The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody

Blood ◽

10.1182/blood-2010-02-271874 ◽

2010 ◽

Vol 116 (13) ◽

pp. 2286-2294 ◽

Cited By ~ 459

Author(s):

Don M. Benson ◽

Courtney E. Bakan ◽

Anjali Mishra ◽

Craig C. Hofmeister ◽

Yvonne Efebera ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Response ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Cell Immune Response ◽

Cell Versus

Abstract T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti–PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1+ MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.

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A natural killer cell gene signature predicts melanoma patient survival

10.1101/375253 ◽

2018 ◽

Author(s):

Joseph Cursons ◽

Fernando Souza-Fonseca-Guimaraes ◽

Ashley Anderson ◽

Momeneh Foroutan ◽

Soroor Hediyeh-Zadeh ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Solid Tumors ◽

Immune Cell ◽

Nk Cell ◽

Killer Cell ◽

Cell Activity ◽

Human Tumors ◽

The Cancer Genome Atlas ◽

Cell Gene

AbstractAnimal models have demonstrated that natural killer (NK) cells can limit the metastatic dissemination of tumors, however their ability to combat established human tumors has been difficult to investigate.A number of computational methods have been developed for the deconvolution of immune cell types within solid tumors. We have taken the NK cell gene signatures from several tools, then curated and expanded this list using recent reports from the literature. Using a gene set scoring method to investigate RNA-seq data from The Cancer Genome Atlas (TCGA) we show that patients with metastatic cutaneous melanoma have an improved survival rate if their tumor shows evidence of greater NK cell infiltration. Furthermore, these survival effects are enhanced in tumors which have a higher expression of NK cell stimuli such as IL-15, suggesting NK cells are part of a coordinated immune response within these patients. Using this signature we then examine transcriptomic data to identify tumor and stromal components which may influence the penetrance of NK cells into solid tumors.These data support a role for NK cells in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. Furthermore, our computational analysis identifies a number of potential targets which may help to unleash the anti-tumor potential of NK cells as we enter the age of immunotherapy.

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Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽

10.1182/blood.v65.1.65.bloodjournal65165 ◽

1985 ◽

Vol 65 (1) ◽

pp. 65-70 ◽

Cited By ~ 1

Author(s):

HW Ziegler-Heitbrock ◽

H Rumpold ◽

D Kraft ◽

C Wagenpfeil ◽

R Munker ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Target Cells ◽

Nk Cell Activity

Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

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Effect of eccentric exercise on natural killer cell activity

Journal of Applied Physiology ◽

10.1152/jappl.1995.78.4.1442 ◽

1995 ◽

Vol 78 (4) ◽

pp. 1442-1446 ◽

Cited By ~ 15

Author(s):

J. Palmo ◽

S. Asp ◽

J. R. Daugaard ◽

E. A. Richter ◽

M. Klokker ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Eccentric Exercise ◽

Nk Cell ◽

Killer Cell ◽

Cell Activity ◽

Control Group ◽

Systemic Effects ◽

Nk Cell Activity ◽

Blood Samples

The effect of eccentric one-legged exercise on natural killer (NK) cell activity was studied in eight healthy males. To distinguish between local and systemic effects, blood samples were collected from veins in the exercising leg and resting arm. However, the results did not significantly differ between the leg and arm. To eliminate diurnal variations, the results were compared with a control group that did not exercise but had blood samples collected at the same time points. In the exercising group, plasma creatine kinase increased progressively during and up to 4 days after exercise. The percentage of CD16+ NK cells increased during exercise, which was paralleled by an increase in the NK cell activity per fixed number of blood mononuclear cells. The NK cell activity on a per NK cell basis did not change. The percentage of CD3+, CD4+, CD8+, CD19+, and CD14+ cells did not change significantly during exercise. The present study thus showed that eccentric exercise with a relatively small muscle mass (1 quadriceps femoris muscle) causes systemic effects on NK cells. It is suggested that the increase in plasma epinephrine during eccentric exercise is responsible for the observed increase in the percentage of CD16+ cells.

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Effects of β-adrenergic receptor activation, cholera toxin and forskolin on human natural killer cell function

Biochemical Journal ◽

10.1042/bj2720327 ◽

1990 ◽

Vol 272 (2) ◽

pp. 327-331 ◽

Cited By ~ 60

Author(s):

M M Whalen ◽

A D Bankhurst

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cholera Toxin ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

K562 Cells ◽

Receptor Activation ◽

Tumour Cells ◽

Human Natural Killer Cell

Membranes from highly purified natural killer (NK) cells were ADP-ribosylated by treatment with cholera toxin (CTX). CTX resulted in a single band of specific 32P incorporation at Mr 43,600. CTX treatment of intact NK cells caused a 9-fold increase in cyclic AMP (cAMP) concentrations. Pretreatment of NK cells with CTX diminished their ability to lyse K562 tumour cells by up to 79%. Forskolin treatment elevated NK cell cAMP levels 8-fold and decreased lysis of K562 cells by up to 45%. Adrenaline and isoprenaline (isoproterenol) both inhibited lysis of K562 cells by approx. 35% and elevated cAMP by at least 2.5-fold, and their inhibition of lysis was reversed by propranolol. These data suggest that the stimulatory guanine-nucleotide-binding protein GS coupled to beta-adrenergic receptors is involved in transducing signals which inhibit NK cell lysis of tumour cells. CTX and forskolin also diminish the ability of NK cells to bind K562 cells (binding is necessary for lysis). This suggests that the NK-cell receptor(s) for the tumour cell may be altered as a consequence of cAMP-mediated events or by activation of GS.

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Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis

Viruses ◽

10.3390/v13050889 ◽

2021 ◽

Vol 13 (5) ◽

pp. 889

Author(s):

Irene Müller ◽

Lisa Janson ◽

Martina Sauter ◽

Kathleen Pappritz ◽

Sophie Van Linthout ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Acute Myocarditis ◽

Killer Cell ◽

Cell Activity ◽

Suppressor Cells ◽

Coxsackievirus B3 ◽

Myeloid Derived Suppressor Cells ◽

Chronic Myocarditis

Murine models of coxsackievirus B3 (CVB3)-induced myocarditis well represent the different outcomes of this inflammatory heart disease. Previously, we found that CVB3-infected A.BY/SnJ mice, susceptible for severe acute and chronic myocarditis, have lower natural killer (NK) cell levels than C57BL/6 mice, with mild acute myocarditis. There is evidence that myeloid-derived suppressor cells (MDSC) may inhibit NK cells, influencing the course of myocarditis. To investigate the MDSC/NK interrelationship in acute myocarditis, we used CVB3-infected A.BY/SnJ mice. Compared to non-infected mice, we found increased cell numbers of MDSC in the spleen and heart of CVB3-infected A.BY/SnJ mice. In parallel, S100A8 and S100A9 were increased in the heart, spleen, and especially in splenic MDSC cells compared to non-infected mice. In vitro experiments provided evidence that MDSC disrupt cytotoxic NK cell function upon co-culturing with MDSC. MDSC-specific depletion by an anti-Ly6G antibody led to a significant reduction in the virus load and injury in hearts of infected animals. The decreased cardiac damage in MDSC-depleted mice was associated with fewer Mac3+ macrophages and CD3+ T lymphocytes and a reduced cardiac expression of S100A8, S100A9, IL-1β, IL-6, and TNF-α. In conclusion, impairment of functional NK cells by MDSC promotes the development of chronic CVB3 myocarditis in A.BY/SnJ mice.

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Indomethacin inhibits circulating PGE2 and reverses postexercise suppression of natural killer cell activity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.5.r1496 ◽

1999 ◽

Vol 276 (5) ◽

pp. R1496-R1505

Author(s):

Shawn G. Rhind ◽

Greg A. Gannon ◽

Masatoshi Suzui ◽

Roy J. Shephard ◽

Pang N. Shek

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Strenuous Exercise ◽

Double Blind ◽

Cell Counts ◽

Ergometer Exercise

Natural killer (NK) cells are important in combating viral infections and cancer. NK cytolytic activity (NKCA) is often depressed during recovery from strenuous exercise. Lymphocyte subset redistribution and/or inhibition of NK cells via soluble mediators, such as prostaglandin (PG) E2 and cortisol, are suggested as mechanisms. Ten untrained (peak O2 consumption = 44.0 ± 3.5 ml ⋅ kg−1 ⋅ min−1) men completed at 2-wk intervals a resting control session and three randomized double-blind exercise trials after the oral administration of a placebo, the PG inhibitor indomethacin (75 mg/day for 5 days), or naltrexone (reported elsewhere). Circulating CD3−CD16+/56+NK cell counts, PGE2, cortisol, and NKCA were measured before, at 0.5-h intervals during, and at 2 and 24 h after a 2-h bout of cycle ergometer exercise (65% peak O2 consumption). During placebo and indomethacin conditions, exercise induced significant ( P < 0.0001) elevations of NKCA (>100%) and circulating NK cell counts (>350%) compared with corresponding control values. With placebo treatment, total NKCA was suppressed (28%; P < 0.05) 2 h after exercise, and a postexercise elevation (36%; P = 0.02) of circulating PGE2 was negatively correlated ( r = 0.475, P = 0.03) with K-562 tumor cell lysis. NK counts were unchanged in the postexercise period, but at this stage CD14+ monocyte numbers were elevated ( P < 0.0001). Indomethacin treatment eliminated the postexercise increase in PGE2 concentration and completely reversed the suppression of total and per CD16+56+NKCA 2 h after exercise. These data support the hypothesis that the postexercise reduction in NKCA reflects changes in circulating PGE2 rather than a differential lymphocyte redistribution.

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