scholarly journals Placentation and antitumor immunity regulated by a scaffolding protein in NK cells

2019 ◽  
Vol 4 (38) ◽  
pp. eaax9589
Author(s):  
Francesco Colucci
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Adaptor Protein ◽  
Scaffolding Protein ◽  
Trophoblast Invasion ◽  
Related Research ◽  
Research Article

Natural killer cells use the Gab3 adaptor protein to limit trophoblast invasion during pregnancy and to reject tumor cells. See the related Research Article by Sliz et al.

scholarly journals Activation of Natural Killer Cells and Dendritic Cells upon Recognition of a Novel CD99-like Ligand by Paired Immunoglobulin-like Type 2 Receptor

2004 ◽  
Vol 199 (4) ◽  
pp. 525-533 ◽  
Author(s):  
Ikuo Shiratori ◽  
Kouetsu Ogasawara ◽  
Takashi Saito ◽  
Lewis L. Lanier ◽  
Hisashi Arase
Keyword(s):  
Innate Immunity ◽  
Dendritic Cells ◽  
Immune System ◽  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Regulatory Mechanism ◽  
Adaptor Protein ◽  
T Cell Lines

Paired receptors that consist of highly related activating and inhibitory receptors are widely involved in the regulation of the immune system. Here, we report a mouse orthologue of the human activating paired immunoglobulin-like type 2 receptor (PILR) β, which was cloned from a cDNA library of natural killer (NK) cells based on its ability to associate with the DAP12 signaling adaptor protein. The activating PILRβ was expressed not only on NK cells but also on dendritic cells and macrophages. Furthermore, we have identified a novel CD99-like molecule as a ligand for the activating PILRβ and inhibitory PILRα receptors. Transcripts of PILR ligand are present in many tissues, including some T cell lines. Cells expressing the PILR ligand specifically activated NK cells and dendritic cells that express the activating PILRβ. Our findings reveal a new regulatory mechanism of innate immunity by PILR and its CD99-like ligand.

scholarly journals Identification of a subset of murine natural killer cells that mediates rejection of Hh-1d but not Hh-1b bone marrow grafts.

1989 ◽  
Vol 170 (1) ◽  
pp. 191-202 ◽  
Author(s):  
C L Sentman ◽  
J Hackett ◽  
V Kumar ◽  
M Bennett
Keyword(s):  
Bone Marrow ◽  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Bone Marrow Cells ◽  
Immune Functions ◽  
Infected Cells

NK cells demonstrate many immune functions both in vitro and in vivo, including the lysis of tumor or virus-infected cells and the rejection of bone marrow allografts. However it remains unclear whether or not all NK cells can mediate these various functions or if NK cells exist in functionally distinct subsets. We have developed a new NK-specific mAb, SW5E6, which binds to approximately 50% of murine NK cells. The 5E6 antigen identifies a distinct and stable subset of NK cells and is expressed on about one-half of fresh or rIL-2-activated murine NK cells. Both 5E6+ and 5E6- NK cells are capable of lysing YAC-1 tumor cells in vitro and in vivo. By treating animals with SW5E6, we demonstrate that the 5E6+ subset is necessary for the rejection of H-2d/Hh-1d but not H-2b/Hh-1b bone marrow cells. Thus NK cells exist as functionally separable subsets in vivo.

scholarly journals The Role of Natural Killer Cells as a Platform for Immunotherapy in Pediatric Cancers

2019 ◽  
Vol 21 (10) ◽  
Author(s):  
Miriam Santiago Kimpo ◽  
Bernice Oh ◽  
Shawn Lee
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Childhood Cancers ◽  
Killer Cells ◽  
Cell Immunotherapy

Abstract Purpose of Review We aim to review the most recent findings in the use of NK cells in childhood cancers. Recent Findings Natural killer cells are cytotoxic to tumor cells. In pediatric leukemias, adoptive transfer of NK cells can bridge children not in remission to transplant. Interleukins (IL2, IL15) can enhance NK cell function. NK cell-CAR therapy has advantages of shorter life span that lessens chronic toxicities, lower risk of graft versus host disease when using allogeneic cells, ability of NK cells to recognize tumor cells that have downregulated MHC to escape T cells, and possibly less likelihood of cytokine storm. Cytotoxicity to solid tumors (rhabdomyosarcoma, Ewing’s sarcoma, neuroblastoma) is seen with graft versus tumor effect in transplant and in combination with antibodies. Challenges lie in the microenvironment which is suppressive for NK cells. Summary NK cell immunotherapy in childhood cancers is promising and recent works aim to overcome challenges.

scholarly journals Analysis of sphingosine kinase activity in single natural killer cells from peripheral blood

2015 ◽  
Vol 7 (4) ◽  
pp. 392-401 ◽  
Author(s):  
Alexandra J. Dickinson ◽  
Megan Meyer ◽  
Erica A. Pawlak ◽  
Shawn Gomez ◽  
Ilona Jaspers ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Kinase Activity ◽  
Sphingosine Kinase ◽  
Killer Cells ◽  
Pathway Activity

Heterogeneity of sphingosine kinase (SK) pathway activity in natural killer (NK) cells may enable cells to respond effectively to a diverse array of pathogens as well as incipient tumor cells.

Generation of Natural Killer Cells with Enhanced Function from a CRISPR/Cas12a-Edited Induced Pluripotent Stem Cell Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Jung-Il Moon ◽  
Melissa S Chin ◽  
Andrew T Burden ◽  
Steven Sexton ◽  
Kevin Wasko ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Effector Function ◽  
Publicly Traded ◽  
Killer Cells ◽  
Killing Assay ◽  
Induced Pluripotent

Adoptive cell therapy using T cells to treat cancer is efficacious in a number of hematologic malignancies. Recently, natural killer (NK) cells have emerged as an alternative cell type for clinical utility given the low propensity for graft-versus-host disease, thereby making NK cells a potential off-the-shelf cell therapy. NK cells distinguish tumor from healthy tissue via multiple mechanisms, including recognition of stress ligands and loss of MHC class I expression. For instance, KIR mismatching enables allogenic NK cells to kill MHC-positive tumor cells similar to MHC-negative tumor cells. Effector function of allogeneic NK cells are typically diminished by limited functional persistence, as well as tumor-intrinsic immunosuppressive mechanisms, such as TGF-β, a pleiotropic cytokine that inhibits immune effector function. Gene editing, however, can overcome these biological limitations. We hypothesized that knockout of CISH, a negative regulator of IL-2/IL-15 signaling, would improve NK cell effector function, while knockout of the TGF-β receptor gene 2, TGFBR2, would render NK cells resistant to TGF-β mediated suppression. NK cells are typically isolated from either cord blood or peripheral blood of healthy donors but recent advances with induced pluripotent stem cells (iPSCs) allows a nearly unlimited supply of iPSC-derived natural killer cells (iNK). In this study, we used CRISPR/Cas12a to generate edited iPSC lines that were differentiated into CD56+ iNK cells. Specifically, we generated TGFβR2-/-, CISH-/-, and TGFβR2-/-/CISH-/- iPSC clones with bi-allelic gene disruption confirmed by next generation sequencing. Importantly, we also confirmed that the edited clones were pluripotent. In particular, a minimum of 3 clones from each genotype were differentiated to CD56+ iNK cells. After differentiation, >90% of the cells expressed CD56 for all genotypes. Additionally, we observed the expression of canonical natural killer cell markers such as CD16, NKG2A, KIRs, NKp46, NKp44, and NKp30 within this CD56+ population. We tested the effector function of TGFβR2-/-, CISH-/-, and TGFβR2-/-/CISH-/- iNKs in a variety of molecular and functional assays, including a spheroid killing assay and an in vitro serial killing assay. For example, we utilized a SK-OV-3 spheroid killing assay to determine the intrinsic ability for the iNK cells to kill tumor targets following the differentiation process. TGFβR2-/-, CISH-/-, and TGFβR2-/-/CISH-/- iNKs reduce the size of SK-OV-3 ovarian tumor spheroids more effectively than control iNK cells in the presence of exogenous TGF-β. In conclusion, we have established an iPSC editing platform that can generate a near infinite supply of natural killer cells with enhanced tumor killing function, paving the way for future off-the-shelf cell therapies for application to broad oncology indications. Disclosures Moon: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Chin:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Burden:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Sexton:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Wasko:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Nasser:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Antony:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Wong:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Borges:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Morgan:Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Welstead:Editas Medicine: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Hybrid resistance to EL-4 lymphoma cells. I. Characterization of natural killer cells that lyse EL-4 cells and their distinction from marrow-dependent natural killer cells.

1979 ◽  
Vol 150 (3) ◽  
pp. 531-547 ◽  
Author(s):  
V Kumar ◽  
E Luevano ◽  
M Bennett
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Nk Activity ◽  
Spleen Cells ◽  
Lymphoma Cells ◽  
Hybrid Resistance

Natural killer (NK) cells from nonimmunized mice capable of lysing EL-4 (C57BL/6 strain H-2b) tissue culture-adapted lymphoma cells have been analyzed and compared with NK cells which lyse YAC-1 (A-strain, H-2a) lymphoma cells. A correlation was seen in the ability of inbred and B6D2F1 mice to reject C57BL/6 (B6) bone-marrow grafts and the ability of their spleen cells to lyse EL-4 cells in vitro. This suggests that hybrid or hemopoietic histocompatibility antigens, (Hh-1b), relevant in the rejection of B6 stem cells may also be the relevant target structures for the anti-EL-4 NK cells. Certain features of these NK cells are similar to the NK cells reactive against YAC-1 cells. Both types of NK cells are present in athymic nude mice, are not affected by treatment with anti-immunoglobulin plus complement, and are not depleted by techniques that remove macrophages. NK activity against both targets is stimulated 3 d after injection of Corynebacterium parvum, and 24 h after challenge with polyinosinic:polycytidylic acid. Hydrocortisone acetate and cyclophosphamide lead to reduction of NK activity within 2-3 d after administration. However, the anti-YAC and anti-EL-4 NK reactivities differed in several important respects. Treatment of mice with 89Sr, the bone-seeking isotope, to deplete marrow-dependent cells, depleted the anti-YAC-1 but not anti-EL-4 cell functions. Anti-EL-4 NK cells were unaffected by silica particles in vivo or in vitro; the NK cells reactive to EL-4 cells matured functionally much earlier in life (5 d of age) and the function did not decline with age. Irradiated mice reconstituted with syngeneic marrow or spleen cells developed functional NK cells against EL-4 targets before they developed anti-YAC-1 NK cells in their spleen. Thus anti-EL-4 NK cells that express hybrid resistance in vitro appear to differ from anti-YAC-1 NK cells and do not require an intact marrow microenvironment for functional differentiation. Despite differences in the NK-cell types involved in the lysis of YAC-1 and EL-4 cells, these two tumor cells share certain common determinants. This was ascertained both by cold competition and by utilization of YAC-1 and EL-4 cell monolayers as immunoadsorbents. We conclude that Hh-1b is the common antigen present in EL-4 and YAC-1 cells, because B6D2F1 anti-B6 (anti-Hh-1b) cytotoxic T lymphocytes lysed both the tumor cells. Our data suggest that Hh-1b antigen is recognized by both types of NK cells, but that additional determinants must be present on YAC-1 cells. Two models of NK cell lysis compatible with the data are presented.

scholarly journals Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2184
Author(s):  
Valentina Cazzetta ◽  
Sara Franzese ◽  
Claudia Carenza ◽  
Silvia Della Bella ◽  
Joanna Mikulak ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Primary Liver Cancer ◽  
Circulating Antigens ◽  
Direct Cytotoxicity ◽  
Immune Changes

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.

Natural Killer cells and monoclonal antibodies: Two partners for successful antibody dependent cytotoxicity against tumor cells

2021 ◽  
Vol 160 ◽  
pp. 103261
Author(s):  
Mélanie Gauthier ◽  
Caroline Laroye ◽  
Danièle Bensoussan ◽  
Cédric Boura ◽  
Véronique Decot
Keyword(s):  
Monoclonal Antibodies ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Killer Cells

scholarly journals Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shoeib Moradi ◽  
Sanda Stankovic ◽  
Geraldine M. O’Connor ◽  
Phillip Pymm ◽  
Bruce J. MacLachlan ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Human Leukocyte Antigen ◽  
Nk Cells ◽  
Natural Killer ◽  
Crystal Structures ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Functional Differences ◽  
Molecular Bases

AbstractThe closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.

Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4–anaplastic lymphoma kinase gene fusion

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1209-1216 ◽  
Author(s):  
Sandra J. Meech ◽  
Loris McGavran ◽  
Lorrie F. Odom ◽  
Xiayuan Liang ◽  
Lynne Meltesen ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Functional Properties ◽  
Anaplastic Lymphoma Kinase ◽  
Clinical Presentation ◽  
Hematologic Malignancy ◽  
Malignant Cells ◽  
Neoplastic Cells ◽  
Anaplastic Lymphoma

This report describes an unusual extramedullary hematologic malignancy in an 18-month-old child who presented with a capillary leak syndrome that evolved into hyperleukocytosis with malignant cells. The circulating tumor cells did not express an antigen profile typical of any subtype of leukemia commonly observed in children. Tumor cells were CD3−/CD56+; had germline TCRgenes; and strongly expressed CD30, epithelial membrane antigen, and anaplastic lymphoma kinase (ALK) consistent with a null cell anaplastic large cell lymphoma (ALCL). The malignant cells contained a t(2;19)(p23;p13.1) that interrupted ALK and translocated it to the der(19). Reverse transcriptase-polymerase chain reaction and nucleotide sequence analysis revealed fusion of ALK to tropomyosin 4, an ALK fusion partner not described previously in hematologic malignancies. The clinical presentation and phenotypic features of this malignancy were not typical for ALCL because tumor cells expressed both myeloid (CD13, CD33, HLA-DR) and natural killer (NK) cell antigens. The neoplastic cells most resembled NK cells because in addition to being CD3−/CD56+ with germline TCR genes, these cells were CD25+/CD122+/granzyme B+ and possessed the functional properties of immature NK cells. The unusual clinical presentation, immunophenotype, and functional properties of these neoplastic cells suggest that this malignancy may be derived from the putative myeloid-NK precursor cell. Furthermore co-expression of NK and ALCL features supports the concept that a minority of null-ALCL may be derived from NK cells and expands the spectrum of phenotypes that can be seen in tumors produced by ALK fusion proteins.

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