scholarly journals NK cells mediate clearance of CD8+ T cell–resistant tumors in response to STING agonists

2020 ◽  
Vol 5 (45) ◽  
pp. eaaz2738 ◽  
Author(s):  
Christopher J. Nicolai ◽  
Natalie Wolf ◽  
I-Chang Chang ◽  
Georgia Kirn ◽  
Assaf Marcus ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Tumor Control ◽  
Type I ◽  
Dependent Manner ◽  
Tumor Models

Several immunotherapy approaches that mobilize CD8+ T cell responses stimulate tumor rejection, and some, such as checkpoint blockade, have been approved for several cancer indications and show impressive increases in patient survival. However, tumors may evade CD8+ T cell recognition via loss of MHC molecules or because they contain few or no neoantigens. Therefore, approaches are needed to combat CD8+ T cell–resistant cancers. STING-activating cyclic dinucleotides (CDNs) are a new class of immune-stimulating agents that elicit impressive CD8+ T cell–mediated tumor rejection in preclinical tumor models and are now being tested in clinical trials. Here, we demonstrate powerful CDN-induced, natural killer (NK) cell–mediated tumor rejection in numerous tumor models, independent of CD8+ T cells. CDNs enhanced NK cell activation, cytotoxicity, and antitumor effects in part by inducing type I interferon (IFN). IFN acted in part directly on NK cells in vivo and in part indirectly via the induction of IL-15 and IL-15 receptors, which were important for CDN-induced NK activation and tumor control. After in vivo administration of CDNs, dendritic cells (DCs) up-regulated IL-15Rα in an IFN-dependent manner. Mice lacking the type I IFN receptor specifically on DCs had reduced NK cell activation and tumor control. Therapeutics that activate NK cells, such as CDNs, checkpoint inhibitors, NK cell engagers, and cytokines, may represent next-generation approaches to cancer immunotherapy.

scholarly journals NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1342-1351 ◽  
Author(s):  
Zusen Fan ◽  
Ping Yu ◽  
Yang Wang ◽  
Yugang Wang ◽  
May Lynne Fu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Dependent Manner ◽  
Cd8 Cells ◽  
Ifn Γ

Natural killer (NK) cells are generally reported as innate effector cells for killing virally infected and transformed cells. It is unclear how NK cells evoke adaptive immunity to eradicate tumors. We now demonstrate that the TNF superfamily member, LIGHT, known as TNFSF14 and a T-cell costimulatory molecule, is a critical ligand for the activation of NK cells. Herpesvirus entry mediator (HVEM) is expressed on NK cells, and its engagement with LIGHT mediates NK-cell activation. The expression of LIGHT inside tumors leads to rapid rejection in a NK-dependent manner. Both NK and CD8+ cells are essential but not sufficient for the rejection of tumors because mice lacking either population fail to reject the tumor. Interestingly, activated NK cells do not kill tumors directly but can facilitate the priming of tumor-specific CD8+ T cells in an IFN-γ–dependent manner. Conversely, intratumor depletion of either NK cells or IFN-γ during tumor progression disrupts CD8+ cell–mediated tumor rejection, suggesting that the tumor is the essential site for the crosstalk between NK and CD8+ cells. Furthermore, IFNG-deficient NK cells fail to effectively activate CD8+ T cells, suggesting IFN-γ plays an important role in NK-mediated activation of cytotoxic T lymphocytes (CTLs). Our findings establish a direct role for LIGHT in NK activation/expansion and a critical helper role of activated NK cells in priming CD8+ T cells and breaking T-cell tolerance at the tumor site.

scholarly journals P03.24 Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A32.1-A32
Author(s):  
I Truxova ◽  
L Kasikova ◽  
C Salek ◽  
M Hensler ◽  
D Lysak ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Type I ◽  
Danger Signals ◽  
Hla Dr ◽  
Patient Prognosis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c+CD14high cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA- DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL- 15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.Disclosure InformationI. Truxova: None. L. Kasikova: None. C. Salek: None. M. Hensler: None. D. Lysak: None. P. Holicek: None. P. Bilkova: None. M. Holubova: None. X. Chen: None. R. Mikyskova: None. M. Reinis: None. M. Kovar: None. B. Tomalova: None. J.P. Kline: None. L. Galluzzi: None. R. Spisek: None. J. Fucikova: None.

scholarly journals Pro-apoptotic caspase deficiency reveals a cell-extrinsic mechanism of NK cell regulation

2021 ◽  
Author(s):  
Tayla M. Olsen ◽  
Wei Hong Tan ◽  
Arne C. Knudsen ◽  
Anthony Rongvaux
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Nk Cell ◽  
Apoptotic Cell ◽  
Type I ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
A Cell

AbstractRegulated cell death is essential for the maintenance of cellular and tissue homeostasis. In the hematopoietic system, genetic defects in apoptotic cell death generally produce the accumulation of immune cells, inflammation and autoimmunity. In contrast, we found that genetic deletion of caspases of the mitochondrial apoptosis pathway reduces natural killer (NK) cell numbers and makes NK cells functionally defective in vivo and in vitro. Caspase deficiency results in constitutive activation of a type I interferon (IFN) response, due to leakage of mitochondrial DNA and activation of the cGAS/STING pathway. The NK cell defect in caspase-deficient mice is independent of the type I IFN response, but the phenotype is partially rescued by cGAS or STING deficiency. Finally, caspase deficiency alters NK cells in a cell-extrinsic manner. Type I IFNs and NK cells are two essential effectors of antiviral immunity, and our results demonstrate that they are both regulated in a caspase-dependent manner. Beyond caspase-deficient animals, our observations may have implications in infections that trigger mitochondrial stress and caspase-dependent cell death.

scholarly journals XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with Listeria monocytogenes or certain viruses

2015 ◽  
Vol 213 (1) ◽  
pp. 75-92 ◽  
Author(s):  
Yannick O. Alexandre ◽  
Sonia Ghilas ◽  
Cindy Sanchez ◽  
Agnès Le Bon ◽  
Karine Crozat ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Infectious Agent ◽  
Cd8 T Cell ◽  
Dependent Manner ◽  
Secondary Infections

Naive CD8+ T cell priming during tumor development or many primary infections requires cross-presentation by XCR1+ dendritic cells (DCs). Memory CD8+ T lymphocytes (mCTLs) harbor a lower activation threshold as compared with naive cells. However, whether their recall responses depend on XCR1+ DCs is unknown. By using a new mouse model allowing fluorescent tracking and conditional depletion of XCR1+ DCs, we demonstrate a differential requirement of these cells for mCTL recall during secondary infections by different pathogens. XCR1+ DCs were instrumental to promote this function upon secondary challenges with Listeria monocytogenes, vesicular stomatitis virus, or Vaccinia virus, but dispensable in the case of mouse cytomegalovirus. We deciphered how XCR1+ DCs promote mCTL recall upon secondary infections with Listeria. By visualizing for the first time the in vivo choreography of XCR1+ DCs, NK cells and mCTLs during secondary immune responses, and by neutralizing in vivo candidate molecules, we demonstrate that, very early after infection, mCTLs are activated, and attracted in a CXCR3-dependent manner, by NK cell–boosted, IL-12–, and CXCL9-producing XCR1+ DCs. Hence, depending on the infectious agent, strong recall of mCTLs during secondary challenges can require cytokine- and chemokine-dependent cross-talk with XCR1+ DCs and NK cells.

scholarly journals A Contribution of Mouse Dendritic Cell–Derived IL-2 for NK Cell Activation

2004 ◽  
Vol 200 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Francesca Granucci ◽  
Ivan Zanoni ◽  
Norman Pavelka ◽  
Serani L.H. van Dommelen ◽  
Christopher E. Andoniou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Type I Interferons ◽  
Efficient Production ◽  
Type I ◽  
New Information

Dendritic cells (DCs) play a predominant role in activation of natural killer (NK) cells that exert their functions against pathogen-infected and tumor cells. Here, we used a murine model to investigate the molecular mechanisms responsible for this process. Two soluble molecules produced by bacterially activated myeloid DCs are required for optimal priming of NK cells. Type I interferons (IFNs) promote the cytotoxic functions of NK cells. IL-2 is necessary both in vitro and in vivo for the efficient production of IFNγ, which has an important antimetastatic and antibacterial function. These findings provide new information about the mechanisms that mediate DC–NK cell interactions and define a novel and fundamental role for IL-2 in innate immunity.

scholarly journals Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Yan ◽  
Weiwei Chen ◽  
Hua Song ◽  
Xianming Long ◽  
Zhuoya Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I ◽  
Dependent Manner ◽  
Dsdna Antibody

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

scholarly journals Novel APC-like properties of human NK cells directly regulate T cell activation

2015 ◽  
Author(s):  
Jacob Hanna ◽  
Ofer Mandelboim
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Antigen Uptake

Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane-enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell-mediated cytotoxicity and specific ligand recognition by cell surface-activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell-activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell-activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.

scholarly journals Oncolytic virus treatment differentially affects the CD56dim and CD56bright NK cell subsets in vivo and regulates a spectrum of human NK cell activity

2020 ◽  
Author(s):  
Michelle Wantoch ◽  
Erica B. Wilson ◽  
Alastair P. Droop ◽  
Sarah L. Phillips ◽  
Matt Coffey ◽  
...  
Keyword(s):  
Nk Cells ◽  
Oncolytic Virus ◽  
Nk Cell ◽  
Direct Action ◽  
Cell Activity ◽  
Type I ◽  
Dependent Manner ◽  
Nk Cell Activity ◽  
Tumour Immunity

AbstractNatural killer (NK) cells protect against intracellular infection and cancer. These properties are exploited in oncolytic virus (OV) therapy, where anti-viral responses enhance anti-tumour immunity. We have analysed the mechanism by which reovirus, an oncolytic dsRNA virus, modulates human NK cell activity. Reovirus activates NK cells in a type I interferon (IFN-I) dependent manner, resulting in STAT1 and STAT4 signalling in both CD56dim and CD56bright NK cell subsets. Gene expression profiling revealed the dominance of IFN-I responses and identified induction of genes associated with NK cell cytotoxicity and cell cycle progression, with distinct responses in the CD56dim and CD56bright subsets. However, reovirus treatment, acting via IFN-I, inhibited NK cell proliferative responses to IL-15 and was associated with reduced AKT signalling. In vivo, human CD56dim and CD56bright NK cells responded with similar kinetics to reovirus treatment, but CD56bright NK cells were transiently lost from the peripheral circulation at the peak of the IFN-I response, suggestive of their redistribution to secondary lymphoid tissue. These results show that reovirus modulates a spectrum of NK cell activity in vivo, encompassing direct action on tumour cells and the regulation of adaptive immunity. Such activity is likely to mirror NK cell responses to natural viral infection.

Role of fractalkine (CX3CL1) rich neuroblastoma microenvironments for ganglioside GD2 directed immunotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9521-9521
Author(s):  
H. N. Lode ◽  
Y. Zeng ◽  
S. Fest ◽  
G. Gaedicke
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Therapeutic Effect ◽  
Cell Activation ◽  
Nk Cell ◽  
Ganglioside Gd2 ◽  
Ifn Γ

9521 Background: Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form. Methods: We found that FKN is expressed in >90% of 68 neuroblastoma (NB) samples as determined by cDNA microarray analysis. FKN expression was inversely correlated with MYCN amplification, suggesting a higher expression of FKN in MYCN non amplified tumors. We characterized the effect of FKN in the neuroblastoma microenvironment in a mouse model. We demonstrate that FKN released from NB cells mediate migration and adhesion of CD4+-, CD8+- and NK- cells and subsequent secretion of IFN-γ, in vitro and in vivo. However, the presence of FKN in NB microenvironments did not result in significant anti-NB activity. Results: Targeting of IL-2 into the NB microenvironment using anti-ganglioside GD2 antibody cytokine fusion proteins (ch14.18-IL-2) is currently under clinical evaluation. We investigated a the role of FKN in this context. For this purpose, IL-2 was targeted to GD2 positive NB microenvironments secreting FKN. Only mice bearing FKN and IL2 enriched NB microenvironments exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases, in contrast to controls with only FKN or IL-2 enriched NB. This effect was specific since a non-specific antibody-IL-2 fusion protein ch225-IL-2 was ineffective. The mechanisms involved included NK-cell activation by targeted IL-2 into FKN rich NB as indicated by the enhancement of NK-cell mediated lysis using YAC-1 cells as targeted cells. The depletion of NK cells in vivo inhibited the therapeutic effect. Furthermore, co-culture of NXS2-FKN cells and NK cells in vitro induced the expression of IFN-γ by NK cells. However, the depletion of CD8+ T-cells in vivo abrogated the therapeutic effect, and these effector cells showed the highest cytolytic activity against NXS2 target cells in vitro. Finally, only the FKN and IL-2 enriched NB microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. Conclusions: In conclusion our data suggest that targeted IL-2 therapy of FKN rich NB associated with MYCN non-amplified tumors may result in T-cell mediated immune responses. No significant financial relationships to disclose.

scholarly journals NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs

2007 ◽  
Vol 204 (4) ◽  
pp. 893-906 ◽  
Author(s):  
Ulrike Schleicher ◽  
Jan Liese ◽  
Ilka Knippertz ◽  
Claudia Kurzmann ◽  
Andrea Hesse ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Dependent Manner ◽  
Cell Cytotoxicity ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity

Natural killer (NK) cells are sentinel components of the innate response to pathogens, but the cell types, pathogen recognition receptors, and cytokines required for their activation in vivo are poorly defined. Here, we investigated the role of plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs), Toll-like receptors (TLRs), and of NK cell stimulatory cytokines for the induction of an NK cell response to the protozoan parasite Leishmania infantum. In vitro, pDCs did not endocytose Leishmania promastigotes but nevertheless released interferon (IFN)-α/β and interleukin (IL)-12 in a TLR9-dependent manner. mDCs rapidly internalized Leishmania and, in the presence of TLR9, produced IL-12, but not IFN-α/β. Depletion of pDCs did not impair the activation of NK cells in L. infantum–infected mice. In contrast, L. infantum–induced NK cell cytotoxicity and IFN-γ production were abolished in mDC-depleted mice. The same phenotype was observed in TLR9−/− mice, which lacked IL-12 expression by mDCs, and in IL-12−/− mice, whereas IFN-α/β receptor−/− mice showed only a minor reduction of NK cell IFN-γ expression. This study provides the first direct evidence that mDCs are essential for eliciting NK cell cytotoxicity and IFN-γ release in vivo and demonstrates that TLR9, mDCs, and IL-12 are functionally linked to the activation of NK cells in visceral leishmaniasis.

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