scholarly journals Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 85 ◽  
Author(s):  
Jesus Luna ◽  
Steven Grossenbacher ◽  
Ian Sturgill ◽  
Erik Ames ◽  
Sean Judge ◽  
...  
Keyword(s):  
Stem Cell ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Human Tumor ◽  
Growth Delay ◽  
Cell Targeting ◽  
Immunodeficient Mice

Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.

scholarly journals The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans

2009 ◽  
Vol 206 (7) ◽  
pp. 1495-1503 ◽  
Author(s):  
Cameron S. Brandt ◽  
Myriam Baratin ◽  
Eugene C. Yi ◽  
Jacob Kennedy ◽  
Zeren Gao ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Tumor ◽  
Cell Surface Molecule ◽  
B7 Family

Cancer development is often associated with the lack of specific and efficient recognition of tumor cells by the immune system. Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumors. We report the identification of a tumor cell surface molecule that binds NKp30, a human receptor which triggers antitumor NK cell cytotoxicity and cytokine secretion. This previously unannotated gene belongs to the B7 family and, hence, was designated B7-H6. B7-H6 triggers NKp30-mediated activation of human NK cells. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells, emphasizing that the expression of stress-induced self-molecules associated with cell transformation serves as a mode of cell recognition in innate immunity.

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

scholarly journals Natural killer cells suppress human erythroid stem cell proliferation in vitro

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 260-269 ◽  
Author(s):  
KF Mangan ◽  
ME Hartnett ◽  
SA Matis ◽  
A Winkelstein ◽  
T Abo
Keyword(s):  
Stem Cell ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Natural Killer Cell ◽  
Percoll Density Gradient Centrifugation

Abstract To determine the role of natural killer (NK) cells in the regulation of human erythropoiesis, we studied the effects of NK-enriched cell populations on the in vitro proliferation of erythroid stem cells at three different levels of maturation (day 14 blood BFU-E, day 5–6 marrow CFU-E, and day 10–12 marrow BFU-E). NK cells were enriched from blood by Percoll density gradient centrifugation and by fluorescence- activated cell sorting (FACS), using the human natural killer cell monoclonal antibody, HNK-1. The isolated enriched fractions were cocultured with autologous nonadherent marrow cells or blood null cells and erythropoietin in a methylcellulose erythroid culture system. Cells from low-density Percoll fractions (NK-enriched cells) were predominantly large granular lymphocytes with cytotoxic activity against K562 targets 6–10-fold greater than cells obtained from high- density Percoll fractions (NK-depleted cells). In coculture with marrow nonadherent cells (NA) at NK:NA ratios of 2:1, NK-enriched cells suppressed day 5–6 CFU-E to 62% (p less than 0.025) of controls, whereas NK-depleted cells slightly augmented CFU-E to 130% of controls (p greater than 0.05). In contrast, no suppression of day 10–12 marrow BFU-E was observed employing NK-enriched cells. The NK CFU-E suppressor effects were abolished by complement-mediated lysis of NK-enriched cells with the natural killer cell antibody, HNK-1. Highly purified HNK- 1+ cells separated by FACS suppressed marrow CFU-E to 34% (p less than 0.025) and marrow BFU-E to 41% (p less than 0.025) of controls. HNK- cells had no significant effect on either BFU-E or CFU-E growth. NK- enriched cells were poor stimulators of day 14 blood BFU-E in comparison to equal numbers of NK-depleted cells or T cells isolated by E-rosetting (p less than 0.01). Interferon boosting of NK-enriched cells abolished their suboptimal burst-promoting effects and augmented their CFU-E suppressor effects. These studies provide evidence for a potential regulatory role of NK cells in erythropoiesis. The NK suppressor effect is maximal at the level of the mature erythroid stem cell CFU-E. These findings may explain some hypoproliferative anemias that develop in certain NK cell-activated states.

Pluripotent Stem Cell-Derived Human Natural Killer Cells with Potent Anti-Multiple Myeloma Activity,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4034-4034
Author(s):  
David A. Knorr ◽  
Zhenya Ni ◽  
Allison Bock ◽  
Vijay G. Ramakrishnan ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Adoptive Immunotherapy ◽  
Target Cell ◽  
Peripheral Blood ◽  
Nk Cell

Abstract Abstract 4034 Natural Killer (NK) cells are lymphocytes of the innate immune system with anti-viral and anti-cancer activity. Over the past decade, they have gained interest as a promising cellular source for use in adoptive immunotherapy for the treatment of cancer. Most notably, NK cells play an important role in the graft-vs-tumor effect seen in allogeneic hematopoietic stem cell transplantation (allo-HSCT), and a better understanding of NK cell biology has translated into improved transplant outcomes in acute myelogenous leukemia (AML). Small studies have demonstrated a role for NK cell activity in multiple myeloma (MM) patients receiving allo-HSCT. Investigators have also utilized haplo-identical killer immunoglobulin-like receptor (KIR) mismatched NK cells for adoptive immunotherapy in patients with multiple myeloma (MM). Our group has focused on the development of NK cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as a novel starting source of lymphocytes for immunotherapy. We have previously demonstrated potent anti-tumor activity of hESC-derived NK cells in vitro and in vivo against a variety of different targets. We have also shown that iPSC-derived NK cells from a variety of different somatic cell starting sources posses potent anti-tumor and anti-viral activity. Here, we demonstrate hESC- and iPSC-derived NK cell development in a completely defined, feeder-free system that is amenable to clinical scale-up. These cultures contain a pure population of mature NK cells devoid of any T or B cell contamination, which are common adverse bystanders of cellular products isolated and enriched from peripheral blood. Our cultures are homogenous for their expression of CD56 and express high levels of effector molecules known to be important in anti-MM activity, including KIR, CD16, NKG2D, NKp46, NKp44, FasL and TRAIL. We have now tested the activity of hESC- and iPSC-derived NK cells against MM tumor cells in order to provide a universal source of lymphocytes for adoptive immunotherapy in patients with treatment refractory disease. We find that similar to peripheral blood NK cells (PB-NK), hESC- and iPSC-derived NK cells are cytotoxic against 3 distinct MM cell lines in a standard chromium release cytotoxicity assay. Specifically, activated PB-NK cells killed 48.5% of targets at 10 to 1 effector to target ratios, whereas hESC (46.3%) and iPSC (42.4%) derived NK cells also demonstrated significant anti-MM activity. Also, hESC- and iPSC-derived NK cells secrete cytokines (IFNγ and TNFα) and degranulate as demonstrated by CD107a surface expression in response to MM target cell stimulation. When tested against freshly isolated samples from MM patients, hESC- and IPSC-derived NK cells respond at a similar level as activated PB-NK cells, the current source of NK cells used in adoptive immunotherapy trials. These MM targets (both cell lines and primary tumor cells) are known to express defined ligands (MICA/B, DR4/5, ULBP-1, BAT3) for receptors expressed on NK cells as well as a number of undefined ligands for natural cytotoxicity receptors (NCRs) and KIR. As these receptor-ligand interactions drive the anti-MM activity of NK cells, we are currently evaluating expression of each of these molecules on the surface of both the effector and target cell populations. Not only do hESC- and iPSC-derived NK cells provide a unique, homogenous cell population to study these interactions, they also provide a genetically tractable source of lymphocytes for improvement of the graft-vs-myeloma effect and could be tailored on a patient specific basis using banks of hESC-or iPSC-derived NK cells with defined KIR genotypes for use as allogeneic or autologous effector cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 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 ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2286-2294 ◽  
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.

scholarly journals Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Chaopin Yang ◽  
Yue Li ◽  
Yaozhang Yang ◽  
Zhiyi Chen
Keyword(s):  
Immune Function ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Tumor Therapy ◽  
Killer Cell ◽  
Oncolytic Viruses ◽  
Target Area

NK cells are lymphocytes with antitumor properties and can directly lyse tumor cells in a non-MHC-restricted manner. However, the tumor microenvironment affects the immune function of NK cells, which leads to immune evasion. This may be related to the pathogenesis of some diseases. Therefore, great efforts have been made to improve the immunotherapy effect of natural killer cells. NK cells from different sources can meet different clinical needs, in order to minimize the inhibition of NK cells and maximize the response potential of NK cells, for example, modification of NK cells can increase the number of NK cells in tumor target area, change the direction of NK cells, and improve their targeting ability to malignant cells. Checkpoint blocking is also a promising strategy for NK cells to kill tumor cells. Combination therapy is another strategy for improving antitumor ability, especially in combination with oncolytic viruses and nanomaterials. In this paper, the mechanisms affecting the activity of NK cells were reviewed, and the therapeutic potential of different basic NK cell strategies in tumor therapy was focused on. The main strategies for improving the immune function of NK cells were described, and some new strategies were proposed.

Assessment of PD-1 expression in human resting and activated natural killer cells and murine tumor models.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 36-36
Author(s):  
Sean J. Judge ◽  
Cordelia Dunai ◽  
Ian R. Sturgill ◽  
Kevin M. Stoffel ◽  
William J. Murphy ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Ex Vivo ◽  
Fold Increase ◽  
Wild Type ◽  
Immunodeficient Mice

36 Background: Blockade of the PD-1/PD-L1/2 axis has revolutionized cancer therapy. Although reinvigorated PD-1+ T cells are the main effectors in the response to checkpoint blockade, the contribution of Natural Killer (NK) cells to PD-1/PD-L1 inhibition is under debate. While PD-1 has been identified on NK cells, this appears to be restricted to small populations under limited conditions. We sought to evaluate the extent of PD-1 expression in mouse and human resting and activated NK cells. Methods: Human NK cells were isolated from healthy donor PBMCs and cancer patients. Ex vivo activation and proliferation techniques included recombinant human cytokine and feeder line co-culture. Murine NK cells were isolated from splenocytes, and PBMCs from wild type and immunodeficient mice. We assessed NK cell surface markers and intracellular cytokine by flow cytometry, and gene expression by quantitative RT-PCR. Results: Over 21-days of ex vivo expansion, expression of PD-1 or PD-L1 on human NK cells was < 1% at all time points, while TIGIT+ expression increased to > 85%. Conversely, ConA stimulation of T cells increased PD-1 expression with no change in TIGIT expression. QRT-PCR demonstrated absent PD-1 expression in purified NK cells compared to a 5-fold increase in PD-1 gene expression in ConA stimulated PBMCs. PD-1/PD-L1 was also < 1% in the NK92 cell line and < 2.5% in peripheral CD56+CD3- NK cells from patients with soft tissue sarcoma (STS). NK cells from digested freshly resected STS show variable PD-1 ( < 10%) and minimal PD-L1 ( < 1%) expression with a small, but measurable population of intra-tumoral NK cells (1% of immune cells). In vivo mouse studies showed < 5% PD-1+ NK cells in spleen and tumor of CT26 tumor-bearing mice, while PD-L1+ NK cells increased in frequency from spleen (5-35%) to tumor (40-95%) in both wild type BALB/C and SCID mice. Conclusions: In contrast to prior studies, we did not observe a substantial PD-1+ population on human or murine NK cells after multiple activation strategies compared to T cells. Contrary to its application in T cells, our data suggest that PD-1 is not a useful marker for NK cell exhaustion/dysfunction. PD-L1 on NK cells may represent an important link between NK and T cell immunotherapy.

scholarly journals Identification of the earliest natural killer cell–committed progenitor in murine bone marrow

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5439-5447 ◽  
Author(s):  
John W. Fathman ◽  
Deepta Bhattacharya ◽  
Matthew A. Inlay ◽  
Jun Seita ◽  
Holger Karsunky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Fate ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Lineage Commitment ◽  
Color Flow ◽  
Cell Commitment

Abstract Natural killer (NK) cells develop in the bone marrow and are known to gradually acquire the ability to eliminate infected and malignant cells, yet the cellular stages of NK lineage commitment and maturation are incompletely understood. Using 12-color flow cytometry, we identified a novel NK-committed progenitor (pre-NKP) that is a developmental intermediate between the upstream common lymphoid progenitor and the downstream NKP, previously assumed to represent the first stage of NK lineage commitment. Our analysis also refined the purity of NKPs (rNKP) by 6-fold such that 50% of both pre-NKP and rNKP cells gave rise to NKp46+ NK cells at the single-cell level. On transplantation into unconditioned Rag2−/−Il2rγc−/− recipients, both pre-NKPs and rNKPs generated mature NK cells expressing a repertoire of Ly49 family members that degranulated on stimulation ex vivo. Intrathymic injection of these progenitors, however, yielded no NK cells, suggesting a separate origin of thymic NK cells. Unlike the rNKP, the pre-NKP does not express IL-2Rβ (CD122), yet it is lineage committed toward the NK cell fate, adding support to the theory that IL-15 signaling is not required for NK commitment. Taken together, our data provide a high-resolution in vivo analysis of the earliest steps of NK cell commitment and maturation.

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