scholarly journals Killer cell Ig-like receptors ligand-mismatched, alloreactive natural killer cells lyse primary solid tumors

Cancer ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 640-648 ◽  
Author(s):  
Francesca Re ◽  
Carlo Staudacher ◽  
Loris Zamai ◽  
Viviana Vecchio ◽  
Marco Bregni
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Killer Cell ◽  
Killer Cells

123 Natural killer cells engineered with an inducible, responsive genetic construct targeting TIGIT and CD73 to relieve immunosuppression within the GBM microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A133-A134
Author(s):  
Kyle Lupo ◽  
Sandro Matosevic
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Nk Cell ◽  
Killer Cell ◽  
Functional Responses ◽  
Killer Cells ◽  
Genetic Construct

BackgroundSolid tumors such as GBM are particularly difficult to treat, being largely resistant to traditional treatments, fueling interest in alternative treatment approaches, including cell-based immunotherapy. Natural killer (NK) cells have emerged as promising effectors to target GBM through genetic modifications and ex vivo manipulation. However, immunosuppressive conditions within the tumor microenvironment (TME) further complicate NK cell-based treatments. Specifically, within the TME tumor cells release of high levels of ATP extracellularly. While intracellular ATP is necessary for cell metabolism, extracellular ATP is converted into adenosine (ADO) by ectonucleotidases CD39 and CD73, both overexpressed on GBM.1 Extracellular ADO induces immunometabolic suppression of NK cells through binding with A2A adenosine receptors (A2ARs) on NK cells, suppressing cytokine secretion, proliferation, and other functional activities. 2–4 Adding to the suppression of NK cells is the interaction between CD155, expressed highly on GBM and other solid tumors, and T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on NK cells. This interaction signals inhibition of NK cell cytolytic function, allowing for cancer cell immune-evasion.5,6MethodsTo restore impaired NK cell anti-tumor activity, we have engineered NK cells to concomitantly target CD155 and CD73-induced immunosuppression on GBM using a tumor-responsive genetic construct. The construct is capable of blocking the immunosuppressive CD155/TIGIT interaction, and, upon binding, release a CD73-blocking scFv to inhibit the accumulation of extracellular ADO and mitigate immunosuppression of NK cells. Such localized response enhances specificity and reduces off-target effects of NK-based targeting.ResultsPrimary NK cells were successfully electroporated to express our synthetic TIGIT-synNotch construct, as evidenced by increased expression levels of TIGIT (% and MFI) (figure 1). To evaluate the functionality of engineered NK cells against GBM targets, we tested the cytotoxicity of our engineered NK cells against a primary, patient-derived GBM cell line, GBM43. Overall, cytolytic function of engineered NK cells against GBM was significantly higher than that of non-engineered NK cells, with or without CD73 (10 ug/mL) and TIGIT (50 ug/mL) antibodies, for E:T ratios of 5:1 and 10:1 (figure 2), demonstrating the functional efficacy of our genetic construct. Further, engineered NK cells (T-PNK) expressed significantly higher levels of CD107a in response to GBM43 stimulation than non-engineered PNK at E:T ratios 2.5:1 and 10:1 (figure 3).Abstract 123 Figure 1TIGIT-synNotch gene expressionGene expression (left: %, right, MFI) of electroporated NK cells engineered with anti-CD73 and TIGIT blocking mRNAAbstract 123 Figure 2Engineered NK cell cytotoxicityCytotoxicity of NK cells against GBM43 cells at E:T ratios of 2.5:1, 5:1, and 10:1. NK cells were either un-transfected (with and without CD73 and TIGIT mAbs), transfected with the TIGIT-synNotch construct, or transfected with the TIGIT-synNotch and CD73 genetic constructsAbstract 123 Figure 3Engineered NK cell degranulationCD107a expression measured on transfected and non-transfected NK cells stimulated with GBM43 at E:T ratios of 2.5:1, 5:1, and 10:1ConclusionsOverall, we have shown that co-targeting CD155 and CD73 in a localized, responsive manner can dampen immunosuppression and significantly enhance the killing potential of engineered NK cells against aggressive patient-derived GBM tumors.ReferencesChambers AM, et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front. Immunol 2018;9:2533.Chambers AM, Lupo KB & Matosevic S. Tumor microenvironment-induced immunometabolic reprogramming of natural killer cells. Front Immunol 2018;9:2517.Chambers AM, et al. Adenosinergic signaling alters natural killer cell functional responses. Front. Immunol 2018;9:2533.Wang, J., Lupo, K. B., Chambers, A. M. & Matosevic, S. Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J. immunotherapy cancer 2018;6:136.Zhang B, et al. Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155. Cancer Immunol Immunother 2016;65:305–314.Lupo KB & Matosevic S. CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma. J Hematol Oncol 2020;13:76.

scholarly journals 130 Engineered natural killer cells reactively block TIGIT and CD73 in the GBM microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A139-A139
Author(s):  
Kyle Lupo ◽  
Sandro Matosevic
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Nk Cell ◽  
Killer Cell ◽  
Functional Responses ◽  
Killer Cells ◽  
Genetic Construct

BackgroundNatural killer (NK) cells have emerged as promising effectors to target GBM and other solid tumors through genetic modifications and ex vivo manipulation. However, immunosuppressive conditions within the tumor microenvironment (TME) and interactions between NK cell activating and inhibitory receptors further complicate NK cell-based treatments. In particular, the T cell immunoreceptor with Ig and ITIM domains (TIGIT) is expressed on NK cells and interacts with CD155 to induce immunosuppression of NK cell cytolytic functions.1 2 Although CD155 also binds with activating receptors DNAM-1 and CD96 on NK cells, spurring NK cell activity, TIGIT has predominantly been reported as having an inhibitory effect on NK cells.3–5 Further, tumor cells release of high levels of ATP extracellularly. While intracellular ATP is necessary for cell metabolism, extracellular ATP is converted into adenosine (ADO) by ectonucleotidases CD39 and CD73, both overexpressed on GBM and other solid tumors.6 Extracellular ADO induces immunometabolic suppression of NK cells through binding with A2A adenosine receptors (A2ARs) on NK cells, suppressing cytokine secretion, proliferation, and other functional activities.7–9 We found that TIGIT and CD73 are effective combination targets in GBM for both primary and iPSC-derived NK cells.MethodsIn order to effectively target immunometabolic reprogramming induced by CD73-produced adenosine and the immunosuppressive TIGIT-CD155 axis, we have engineered NK cells to concomitantly target CD155 and CD73-induced immunosuppression on GBM using a tumor-responsive genetic construct based on the synNotch signaling system. The construct is capable of blocking the immunosuppressive CD155/TIGIT interaction, and, upon binding, release a CD73-blocking scFv to inhibit the accumulation of extracellular ADO and mitigate immunosuppression of NK cells. Such localized response enhances specificity and reduces off-target effects of NK-based targeting.ResultsPrimary NK cells and iPSC-derived NK cells were successfully engineered to express the synthetic TIGIT-synNotch construct, measured through expression of TIGIT. To evaluate the functionality of engineered NK cells against GBM targets, we tested the cytotoxicity of our engineered NK cells against a primary, patient-derived GBM cell line, GBM43. Overall, cytolytic function of engineered NK cells against GBM was significantly higher than that of non-engineered NK cells, with or without CD73 (10 ug/mL) and TIGIT (50 ug/mL) antibodies, for E:T ratios of 5:1 and 10:1, demonstrating the functional efficacy of our genetic construct.ConclusionsOverall, we have shown that co-targeting CD155 and CD73 in a localized, responsive manner can dampen immunosuppression and significantly enhance the killing potential of engineered NK cells against aggressive patient-derived GBM tumors.ReferencesZhang B, et al. Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155. Cancer Immunol Immunother 2016;65:305–314.Lupo KB & Matosevic S. CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma. J Hematol Oncol 2020;13:76.Hung AL, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. OncoImmunology 2018; e1466769. doi:10.1080/2162402X.2018.1466769.Mahnke K & Enk, AH. TIGIT-CD155 Interactions in Melanoma: A Novel Co-Inhibitory Pathway with Potential for Clinical Intervention. Journal of Investigative Dermatology 2016; 136, 9–11.Stanietsky N, et al. Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR: Innate immunity. Eur J Immunol 2013; 43:2138–2150.Chambers AM, et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front Immunol 2018;9:2533.Chambers AM, Lupo KB & Matosevic S. Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells. Front Immunol 2018;9:2517.Chambers AM. et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front Immunol 2018;9:2533.Wang J, Lupo KB, Chambers AM & Matosevic S. Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J Immunotherapy Cancer 2018;6:136.Ethics ApprovalPrimary human NK cells were obtained from healthy adult donors approved under Purdue University’s Institutional Review Board (IRB) (IRB-approved protocol #1804020540). Donors gave written informed consent prior to taking part in the study.

Nigella sativa and Cancer: A Review Focusing on Breast Cancer, Inhibition of Metastasis and Enhancement of Natural Killer Cell Cytotoxicity

2020 ◽  
Vol 21 (12) ◽  
pp. 1176-1185 ◽  
Author(s):  
Tuğcan Korak ◽  
Emel Ergül ◽  
Ali Sazci
Keyword(s):  
Breast Cancer ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Therapeutic Potential ◽  
Nigella Sativa ◽  
Killer Cell ◽  
B Cell Lymphoma ◽  
Killer Cells ◽  
Natural Killer Cell Cytotoxicity ◽  
Endothelial Growth Factor

Background: In the last decade, there have been accumulating data that the use of medicinal plants could bring additional benefits to the supportive treatment of various diseases. Nigella sativa (N. sativa, family Ranunculaceae) is one of these plants that has attracted considerable interest. The extracts and seeds of N. sativa and its active component thymoquinone have been studied extensively and the results suggest that N. sativa might carry some therapeutic potential for many diseases, including cancer. Methods: The selection criteria for references were applied through Pubmed with “N. sativa and cancer”, “N. sativa and breast cancer”, “N. sativa and metastasis”, “N. sativa and cytotoxicity of natural killer cells”. The pathway analysis was performed using the PANTHER tool by using five randomly selected N. sativa affected genes (Cyclin D1, P53, p21 protein (Cdc42/Rac) activated kinase 1 (PAK1), B-cell lymphoma 2 (Bcl-2) and vascular endothelial growth factor (VEGF)) in order to elucidate further potentially affected signaling pathways. Results: The aim of this review was to summarize studies regarding the effects of N. sativa in cancer generally, with a focus on breast cancer, its anti-metastatic effects, and how N. sativa modulates the cytotoxicity of Natural Killer cells that play a crucial role in tumor surveillance. Conclusion: In summary, the data suggest that N. sativa might be used for its anti-cancer and antimetastatic properties and as an immune system activator against cancer.

scholarly journals Targeting natural killer cells in solid tumors

2019 ◽  
Vol 16 (5) ◽  
pp. 415-422 ◽  
Author(s):  
Guillaume Habif ◽  
Adeline Crinier ◽  
Pascale André ◽  
Eric Vivier ◽  
Emilie Narni-Mancinelli
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Killer Cells

Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal‐Immunotherapy Efficiency of Solid Tumors

Small ◽  
2019 ◽  
Vol 15 (42) ◽  
pp. 1902636 ◽  
Author(s):  
Da Zhang ◽  
Youshi Zheng ◽  
Ziguo Lin ◽  
Shanyou Lan ◽  
Xiaolong Zhang ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Killer Cells ◽  
Powerful Strategy

Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation

2014 ◽  
Vol 31 (3) ◽  
pp. 157-164 ◽  
Author(s):  
Casimir de Rham ◽  
Karine Hadaya ◽  
Cédric Bandelier ◽  
Sylvie Ferrari-Lacraz ◽  
Jean Villard
Keyword(s):  
Kidney Transplantation ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Cmv Infection ◽  
Killer Cells

Molecular basis of human natural killer cell recognition of HLA-E (human leucocyte antigen-E) and its relevance to clearance of pathogen-infected and tumour cells

2000 ◽  
Vol 99 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Christopher A. O'CALLAGHAN
Keyword(s):  
Endoplasmic Reticulum ◽  
Natural Killer Cells ◽  
Natural Killer Cell ◽  
Cell Surface ◽  
Natural Killer ◽  
Human Leucocyte Antigen ◽  
Killer Cell ◽  
Tumour Cells ◽  
Leader Peptide ◽  
Killer Cells

HLA-E (human leucocyte antigen-E) is a conserved class I major histocompatibility molecule which has only limited polymorphism. It binds to the leader peptide derived from the polymorphic classical major histocompatibility molecules HLA-A, HLA-B and HLA-C. This peptide binding is highly specific and stabilizes the HLA-E protein, allowing it to migrate to the cell surface. A functioning TAP (transporter associated with antigen processing) molecule is required to transport these peptides into the endoplasmic reticulum, where they can interact with HLA-E. HLA-E then migrates to the cell surface, where it interacts with CD94/NKG2A receptors on natural killer cells. This interaction inhibits natural killer cell-mediated lysis of a cell displaying HLA-E. If the leader peptide is not present in the endoplasmic reticulum, HLA-E is unstable and is degraded before it reaches the cell surface. In damaged cells, such as virally infected or tumour cells, down-regulation of HLA-A, HLA-B and HLA-C production or inhibition of TAP prevents stabilization of HLA-E by the leader peptide. Under these circumstances, HLA-E does not reach the cell surface and the cell is then vulnerable to lysis by natural killer cells. The molecular mechanisms underlying this function of HLA-E have been revealed by crystallographic studies of the structure of HLA-E.

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