NK Cell Anti-Tumor Surveillance in a Myeloid Cell-Shaped Environment

NK cells are innate lymphoid cells endowed with cytotoxic capacity that play key roles in the immune surveillance of tumors. Increasing evidence indicates that NK cell anti-tumor response is shaped by bidirectional interactions with myeloid cell subsets such as dendritic cells (DCs) and macrophages. DC-NK cell crosstalk in the tumor microenvironment (TME) strongly impacts on the overall NK cell anti-tumor response as DCs can affect NK cell survival and optimal activation while, in turn, NK cells can stimulate DCs survival, maturation and tumor infiltration through the release of soluble factors. Similarly, macrophages can either shape NK cell differentiation and function by expressing activating receptor ligands and/or cytokines, or they can contribute to the establishment of an immune-suppressive microenvironment through the expression and secretion of molecules that ultimately lead to NK cell inhibition. Consequently, the exploitation of NK cell interaction with DCs or macrophages in the tumor context may result in an improvement of efficacy of immunotherapeutic approaches.

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Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells

Blood ◽

10.1182/blood.v97.9.2625 ◽

2001 ◽

Vol 97 (9) ◽

pp. 2625-2632 ◽

Cited By ~ 96

Author(s):

Francesco Colucci ◽

Sandrine I. Samson ◽

Rodney P. DeKoter ◽

Olivier Lantz ◽

Harinder Singh ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Fetal Liver ◽

Myeloid Cell ◽

Cell Development ◽

Stringent Requirement ◽

Nk Cell Differentiation ◽

Ets Family

Abstract PU.1 is a member of the Ets family of transcription factors required for the development of various lymphoid and myeloid cell lineages, but its role in natural killer (NK) cell development is not known. The study shows that PU.1 is expressed in NK cells and that, on cell transfer into alymphoid Rag2/γc−/−mice, hematopoietic progenitors of PU.1−/−fetal liver cells could generate functional NK cells but not B or T cells. Nevertheless, the numbers of bone marrow NK cell precursors and splenic mature NK cells were reduced compared to controls. Moreover,PU.1−/− NK cells displayed reduced expression of the receptors for stem cell factor and interleukin (IL)-7, suggesting a nonredundant role for PU.1 in regulating the expression of these cytokine receptor genes during NK cell development.PU.1−/− NK cells also showed defective expression of inhibitory and activating members of the Ly49 family and failed to proliferate in response to IL-2 and IL-12. Thus, despite the less stringent requirement for PU.1 in NK cell development compared to B and T cells, PU.1 regulates NK cell differentiation and homeostasis.

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NK Cell Interaction With Platelets and Myeloid Cells in the Tumor Milieu

Frontiers in Immunology ◽

10.3389/fimmu.2020.608849 ◽

2020 ◽

Vol 11 ◽

Author(s):

Stefanie Maurer ◽

Lucas Ferrari de Andrade

Keyword(s):

Nk Cells ◽

Tumor Cells ◽

Nk Cell ◽

Germ Line ◽

Immune Surveillance ◽

Myeloid Cells ◽

Cell Interaction ◽

Underlying Mechanisms ◽

Antigen Presenting ◽

Surveillance Mechanism

Natural killer (NK) cells recognize and kill tumor cells via germ-line encoded receptors and polarized degranulation of cytotoxic molecules, respectively. As such, NK cells help to inhibit the development of cancers. The activating receptor NKG2D induces NK cell-mediated killing of metastasizing tumor cells by recognition of the stress-induced ligands MICA, MICB, and ULBP1-6. However, platelets enable escape from this immune surveillance mechanism by obstructing the interactions between NK cells and tumor cells or by cleaving the stress-induced ligands. It is also being increasingly appreciated that NK cells play additional roles in cancer immunity, including chemokine-mediated recruitment of antigen presenting cells in the tumor microenvironment that is followed by generation of adaptive immunity. However, the NK cell interplays with dendritic cells, and macrophages are extremely complex and involve molecular interactions via NKG2D and cytokine receptors. Specifically, NKG2D-mediated chronic interaction between NK cells and tumor-infiltrating macrophages causes immune suppression by differentiating NK cells toward a dysfunctional state. Here we discuss the underlying mechanisms of NK cell control by platelets and myeloid cells with focus on NKG2D and its ligands, and provide a timely perspective on how to harness these pathways with novel immunotherapeutic approaches.

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Prospects for NK Cell Therapy of Sarcoma

Cancers ◽

10.3390/cancers12123719 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3719

Author(s):

Mieszko Lachota ◽

Marianna Vincenti ◽

Magdalena Winiarska ◽

Kjetil Boye ◽

Radosław Zagożdżon ◽

...

Keyword(s):

Nk Cells ◽

Molecular Mechanisms ◽

Cell Function ◽

Nk Cell ◽

Immune Surveillance ◽

Current Treatment ◽

Lymphoid Cells ◽

Current Evidence ◽

Treatment Regimens ◽

Novel Therapeutic Strategies

Natural killer (NK) cells are innate lymphoid cells with potent antitumor activity. One of the most NK cell cytotoxicity-sensitive tumor types is sarcoma, an aggressive mesenchyme-derived neoplasm. While a combination of radical surgery and radio- and chemotherapy can successfully control local disease, patients with advanced sarcomas remain refractory to current treatment regimens, calling for novel therapeutic strategies. There is accumulating evidence for NK cell-mediated immunosurveillance of sarcoma cells during all stages of the disease, highlighting the potential of using NK cells as a therapeutic tool. However, sarcomas display multiple immunoevasion mechanisms that can suppress NK cell function leading to an uncontrolled tumor outgrowth. Here, we review the current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis, as well as the molecular mechanisms behind sarcoma-mediated NK cell suppression. Further, we apply this basic understanding of NK–sarcoma crosstalk in order to identify and summarize the most promising candidates for NK cell-based sarcoma immunotherapy.

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When and how NK cell-induced programmed cell death benefits immunological protection against intracellular pathogen infection

Innate Immunity ◽

10.1177/1753425918800200 ◽

2018 ◽

Vol 24 (8) ◽

pp. 452-465 ◽

Cited By ~ 3

Author(s):

José E Belizário ◽

Jennifer M Neyra ◽

Maria Fernanda Setúbal Destro Rodrigues

Keyword(s):

Cell Death ◽

Nk Cells ◽

Cell Biology ◽

Cell Activation ◽

Nk Cell ◽

Immune Surveillance ◽

Lymphoid Cells ◽

Activated T Cells ◽

Infected Cells ◽

Immunological Protection

NK cells are innate lymphoid cells that exert a key role in immune surveillance through the recognition and elimination of transformed cells and viral, bacterial, and protozoan pathogen-infected cells without prior sensitization. Elucidating when and how NK cell-induced intracellular microbial cell death functions in the resolution of infection and host inflammation has been an important topic of investigation. NK cell activation requires the engagement of specific activating, co-stimulatory, and inhibitory receptors which control positively and negatively their differentiation, memory, and exhaustion. NK cells secrete diverse cytokines, including IFN-γ, TNF-α/β, CD95/FasL, and TRAIL, as well as cytoplasmic cytotoxic granules containing perforin, granulysin, and granzymes A and B. Paradoxically, NK cells also kill other immune cells like macrophages, dendritic cells, and hyper-activated T cells, thus turning off self-immune reactions. Here we first provide an overview of NK cell biology, and then we describe and discuss the life–death signals that connect the microbial pathogen sensors to the inflammasomes and finally to cell death signaling pathways. We focus on caspase-mediated cell death by apoptosis and pro-inflammatory and non-caspase-mediated cell death by necroptosis, as well as inflammasome- and caspase-mediated pyroptosis.

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Involvement of NFAT Signaling in Function and Anti-Tumor Reactivity of NK Cells

Blood ◽

10.1182/blood.v120.21.1887.1887 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1887-1887

Author(s):

Julia S Wild ◽

Benjamin J Schmiedel ◽

Melanie Märklin ◽

Lothar Kanz ◽

Martin R Müller ◽

...

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Conflicts Of Interest ◽

Clinical Success ◽

Immunosuppressive Treatment ◽

Cell Development ◽

Lymphoid Cells ◽

Inosine Monophosphate Dehydrogenase ◽

And Function

Abstract Abstract 1887 NK cells play an important role in anti-tumor immunity. They significantly contribute to the clinical success of allogeneic stem cell transplantation (SCT). Their reactivity as a consequence of an integrative response mediated by various activating and inhibitory surface receptors results in the induction of yet only partially defined signal transduction pathways. One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells). While its role in T cell development and function is meanwhile well defined, surprisingly little is known on its function in NK cells. NFAT seems to be dispensable for NK cell development, but several lines of evidence clearly point to its involvement in NK reactivity and function. Cyclosporin A (CsA) and tacrolimus are immunosuppressive drugs that are widely used in transplant medicine. They mediate their immunosuppressive effects through inhibition of the serine/threonine phosphatase calci-neurin, which dephosphorylates and thereby activates NFAT. Here we studied the role of NFAT in NK cells and found that all five NFAT family members are expressed in NK cells with their levels being dependent on NK cell activation state. CsA and tacrolimus, but not mycophenolic acid which mediates its immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase, reduced activation and degranulation of NK cells, resulting in impaired cytotoxicity and IFN-γ production in response to leukemia targets. NK reactivity was also suppressed by the specific NFAT inhibitors VIVIT and INCA-6, indicating that the calcineurin inhibitors CsA and tacrolimus in fact modulate NK reactivity by inhibition of NFAT proteins and not by potential “off target”-effects. These results provide evidence for the critical involvement of the transcription factor NFAT in NK cell reactivity and also indicate that potential effects on NK cell immunosurveillance should be considered upon choice and dosing of immunosuppressive treatment regimens after SCT. Disclosures: No relevant conflicts of interest to declare.

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Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

Blood Advances ◽

10.1182/bloodadvances.2017008839 ◽

2017 ◽

Vol 1 (27) ◽

pp. 2679-2691 ◽

Cited By ~ 12

Author(s):

Ana Raykova ◽

Paolo Carrega ◽

Frank M. Lehmann ◽

Robert Ivanek ◽

Vanessa Landtwing ◽

...

Keyword(s):

Cell Differentiation ◽

Nk Cells ◽

Nk Cell ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Human Type ◽

Key Points ◽

Nk Cell Differentiation ◽

Cytokine Stimulation ◽

Type 3

Key Points Human type 3 ILCs acquire features of early differentiated NK cells upon cytokine stimulation. IL-12 and IL-15–differentiated human ILC3s acquire cytotoxicity and kill leukemic targets.

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Human Cytokine-Induced Memory-Like Natural Killer Cells

Journal of Innate Immunity ◽

10.1159/000382019 ◽

2015 ◽

Vol 7 (6) ◽

pp. 563-571 ◽

Cited By ~ 42

Author(s):

Melissa M. Berrien-Elliott ◽

Julia A. Wagner ◽

Todd A. Fehniger

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Molecular Mechanisms ◽

Nk Cell ◽

Hematologic Malignancies ◽

Lymphoid Cells ◽

Cell Memory ◽

And Function ◽

Activation Event ◽

Cell Effector

Natural killer (NK) cells are innate lymphoid cells that are important for host defense against infection and mediate antitumor responses. Recent reports from several laboratories have identified that NK cells can remember a prior activation event and consequently respond more robustly when restimulated, a property termed innate NK cell memory. NK cell memory has now been identified following hapten exposure, viral infection, and combined cytokine preactivation with IL-12, IL-15, and IL-18. Many questions in the field remain regarding the cellular and molecular mechanisms regulating memory NK cells and their responses, as well as their formation and function in mice and humans. Here we review our current understanding of cytokine-induced memory-like (CIML) NK cells that are generated by combined preactivation with IL-12, IL-15, and IL-18. These cells exhibit enhanced NK cell effector functions weeks after the initial cytokine preactivation. Further, we highlight the preclinical rationale and ongoing therapeutic application of CIML NK cells for adoptive immunotherapy in patients with hematologic malignancies.

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Utilizing Cytokines to Function-Enable Human NK Cells for the Immunotherapy of Cancer

Scientifica ◽

10.1155/2014/205796 ◽

2014 ◽

Vol 2014 ◽

pp. 1-18 ◽

Cited By ~ 37

Author(s):

Rizwan Romee ◽

Jeffrey W. Leong ◽

Todd A. Fehniger

Keyword(s):

Nk Cells ◽

Cell Biology ◽

Nk Cell ◽

Lymphoid Cells ◽

New Approach ◽

Antitumor Potential ◽

Immunotherapy Of Cancer ◽

Molecular Aspects ◽

And Function ◽

Activation Status

Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.

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Expression Regulation and Function of T-Bet in NK Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.761920 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chen Huang ◽

Jiacheng Bi

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Immune Surveillance ◽

T Box ◽

Effector Functions ◽

Mtorc1 Signaling ◽

Ifn Γ ◽

And Function ◽

Innate Lymphocytes

Natural killer (NK) cells are cytotoxic innate lymphocytes that play an important role in immune surveillance. The development, maturation and effector functions of NK cells are orchestrated by the T-box transcription factor T-bet, whose expression is induced by cytokines such as IFN-γ, IL-12, IL-15 and IL-21 through the respective cytokine receptors and downstream JAK/STATs or PI3K-AKT-mTORC1 signaling pathways. In this review, we aim to discuss the expression and regulation of T-bet in NK cells, the role of T-bet in mouse NK cell development, maturation, and function, as well as the role of T-bet in acute, chronic infection, inflammation, autoimmune diseases and tumors.

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Single-Cell Sequencing Reveals the Novel Role of Ezh2 in NK Cell Maturation and Function

Frontiers in Immunology ◽

10.3389/fimmu.2021.724276 ◽

2021 ◽

Vol 12 ◽

Author(s):

Minghang Yu ◽

Ziyang Su ◽

Xuefeng Huang ◽

Xi Wang

Keyword(s):

Nk Cells ◽

Single Cell ◽

Nk Cell ◽

Critical Role ◽

Negative Regulator ◽

Cell Maturation ◽

Transcriptional Signature ◽

Nk Cell Differentiation ◽

Cell Arrest ◽

And Function

Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and exhibit important functional properties in antimicrobial and antitumoral responses. Our previous work indicated that the enhancer of zeste homolog 2 (Ezh2) is a negative regulator of early NK cell differentiation and function through trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK cells and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on the transcriptional signature during NK cell maturation. Conditional deletion of Ezh2 in NK cells resulted in a maturation trajectory toward NK cell arrest in CD11b SP stage 5, which was clustered with genes related to the activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating AP-1 family gene expression independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis in altering the NK cell maturation trajectory and NK cell-mediated cytotoxicity.

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