scholarly journals Pediatric Tumors-Mediated Inhibitory Effect on NK Cells: The Case of Neuroblastoma and Wilms’ Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2374
Author(s):  
Andrea Pelosi ◽  
Piera Filomena Fiore ◽  
Sabina Di Matteo ◽  
Irene Veneziani ◽  
Ignazio Caruana ◽  
...  
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Wilms Tumor ◽  
Suppressor Cells ◽  
Inhibitory Effect ◽  
Cell Contact

Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms’ tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.

scholarly journals Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1577
Author(s):  
Matteo Tanzi ◽  
Michela Consonni ◽  
Michela Falco ◽  
Federica Ferulli ◽  
Enrica Montini ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Autologous Tumor ◽  
Lymphoid Leukemia ◽  
Hematopoietic Stem ◽  
Solid Malignancies

The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients’ myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients’ non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies.

scholarly journals 150 GAIA-102: a new class off-the-shelf allogeneic NK-like cells that can eliminate solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A163-A163
Author(s):  
Yui Harada ◽  
Yoshikazu Yonemitsu
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Adoptive Immunotherapy ◽  
Nk Cell ◽  
Peritoneal Dissemination ◽  
Checkpoint Inhibitors ◽  
Antitumor Effects ◽  
Car T

BackgroundCancer immunotherapy has been established as a new therapeutic category since the recent success of immune checkpoint inhibitors and a type of adoptive immunotherapy, namely chimeric antigen receptor-modified T cells (CAR-T). Although CAR-T demonstrated impressive clinical results, serious adverse effects (cytokine storm and on-target off-tumor toxicity) and undefined efficacy on solid tumors are important issues to be solved. We’ve developed a cutting-edge, simple, and feeder-free method to generate highly activated and expanded human NK cells from peripheral blood (US9404083, PCT/JP2019/012744, PCT/JP2020/012386), and have been conducting further investigation why our new type of NK cells, named as GAIA-102, are so effective to kill malignant cells.MethodsCryopreserved PBMCs purchased from vendors were mixed and processed by using LOVO and CliniMACS® Prodigy (automated/closed systems). CD3+ and CD34+ cells were depleted, and the cells were cultured with high concentration of hIL-2 and 5% UltraGRO® for 14 days in our original closed system. Then, we confirmed the expression of surface markers, CD107a mobilization and cell-mediated cytotoxicity against various tumor cells and normal cells with or without monoclonal antibody drugs in vitro and antitumor effects against peritoneal dissemination model using SKOV3 in vivo.ResultsImportantly, we’ve found that our GAIA-102 exhibited CD3-/CD56bright/CD57- immature phenotype that could kill various tumor cells efficiently from various origins, including Raji cells that was highly resistant to NK cell killing. More importantly, massive accumulation, retention, infiltration and sphere destruction by GAIA-102 were affected neither by myeloid-derived suppressor cells nor regulatory T-lymphocytes. GAIA-102 was also effective in vivo to murine model of peritoneal dissemination of human ovarian cancer; thus, these findings indicate that GAIA-102 has a potential to be an ‘upward compatible’ modality over CAR-T strategy, and would be a new and promising candidate for adoptive immunotherapy against solid tumors.ConclusionsWe now just started GMP/GCTP production of this new and powerful NK cells and first-in-human clinical trials in use of GAIA-102 will be initiated on 2021.Ethics ApprovalThe animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Kyushu University (approval nos. A30-234-0 and A30-359-0).

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 Stromal Cells from Human Decidua Exert a Strong Inhibitory Effect on NK Cell Function and Dendritic Cell Differentiation

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89006 ◽  
Author(s):  
Daniele Croxatto ◽  
Paola Vacca ◽  
Francesca Canegallo ◽  
Romana Conte ◽  
Pier Luigi Venturini ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Dendritic Cell ◽  
Stromal Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Inhibitory Effect ◽  
Dendritic Cell Differentiation ◽  
Strong Inhibitory Effect ◽  
Human Decidua

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 Mononuclear myeloid-derived “suppressor” cells express RAE-1 and activate natural killer cells

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4080-4089 ◽  
Author(s):  
Norman Nausch ◽  
Ioanna E. Galani ◽  
Eva Schlecker ◽  
Adelheid Cerwenka
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing

Abstract Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice and potently suppress T-cell activation. In this study, we investigated whether MDSCs regu-late natural killer (NK)–cell function. We discovered that mononuclear Gr-1+CD11b+F4/80+ MDSCs isolated from RMA-S tumor-bearing mice do not suppress, but activate NK cells to produce high amounts of IFN-γ. Gr-1+CD11b+F4/80+ MDSCs isolated from tumor-bearing mice, but not myeloid cells from naive mice, expressed the ligand for the activating receptor NKG2D, RAE-1. NK-cell activation by MDSCs depended partially on the interaction of NKG2D on NK cells with RAE-1 on MDSCs. NK cells eliminated Gr-1+CD11b+F4/80+ MDSCs in vitro and upon adoptive transfer in vivo. Finally, depletion of Gr-1+ cells that comprise MDSCs confirmed their protective role against the NK-sensitive RMA-S lymphoma in vivo. Our study reveals that MDSCs do not suppress all aspects of antitumor immune responses and defines a novel, unexpected activating role of MDSCs on NK cells. Thus, our results have great impact on the design of immune therapies against cancer aiming at the manipulation of MDSCs.

scholarly journals NK cells switch from granzyme B to death receptor–mediated cytotoxicity during serial killing

2019 ◽  
Vol 216 (9) ◽  
pp. 2113-2127 ◽  
Author(s):  
Isabel Prager ◽  
Clarissa Liesche ◽  
Hanna van Ooijen ◽  
Doris Urlaub ◽  
Quentin Verron ◽  
...  
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Granzyme B ◽  
Death Receptor ◽  
Death Receptors ◽  
Cell Contact ◽  
Cell Death Pathways ◽  
Serial Killing

NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor–mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perforin and increased surface-CD95L in NK cells over time, showing how the switch in cytotoxicity pathways is controlled. Without perforin, NK cells were unable to perform GrzB-mediated serial killing and only killed once via death receptors. In contrast, the absence of CD95 on tumor targets did not impair GrzB-mediated serial killing. This demonstrates that GrzB and death receptor–mediated cytotoxicity are differentially regulated during NK cell serial killing.

scholarly journals NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

2021 ◽  
Vol 12 ◽  
Author(s):  
E Hui Clarissa Lee ◽  
Darren Chen Pei Wong ◽  
Jeak Ling Ding
Keyword(s):  
Transcription Factors ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Early Stage ◽  
Treatment Strategies ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Inhibitory Effect ◽  
Inhibitory Receptors

Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.

scholarly journals CD38 contributes to human natural killer cell responses through a role in immune synapse formation

2018 ◽  
Author(s):  
Mathieu Le Gars ◽  
Christof Seiler ◽  
Alexander W. Kay ◽  
Nicholas L. Bayless ◽  
Elsa Sola ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synapse Formation ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Target Cells ◽  
Immune Synapse ◽  
Ifn Γ

AbstractNatural killer (NK) cells use a diverse array of activating and inhibitory surface receptors to detect threats and provide an early line of defense against viral infections and cancer. Here, we demonstrate that the cell surface protein CD38 is a key human NK cell functional receptor through a role in immune synapse formation. CD38 expression marks a mature subset of human NK cells with a high functional capacity. NK cells expressing high levels of CD38 display enhanced killing and IFN-γ secretion in response to influenza virus-infected and tumor cells. Inhibition of CD38 enzymatic activity does not influence NK cell function, but blockade of CD38 and its ligand CD31 abrogates killing and IFN-γ expression in response to influenza-infected cells. Blockade of CD38 on NK cells similarly inhibits killing of tumor cells. CD38 localizes and accumulates at the immune synapse between NK cells and their targets, and blocking CD38 severely abrogates the ability of NK cells to form conjugates and immune synapses with target cells. Thus, CD38 plays a critical role in NK cell immune synapse formation. These findings open new avenues in immunotherapeutic development for cancer and infection by revealing a critical role for CD38 in NK cell function.

Tumor Cell-Associated Tissue Factor Supports Metastatic Potential through Both NK Cell-Dependent and -Independent Mechanisms.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 66-66 ◽  
Author(s):  
Joseph Palumbo ◽  
Kelley A. Barney ◽  
Matthew J. Flick ◽  
Kathryn E. Talmage ◽  
Keith W. Kombrinck ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Metastatic Potential ◽  
Hemostatic System ◽  
Hemostatic Factors

Abstract Multiple lines of evidence indicate that the hemostatic system contributes to cancer dissemination. Previous studies have shown that tumor cell-associated tissue factor (TF) expression is a crucial determinant of metastatic potential. Furthermore, we have shown that tumor cell-associated TF supports metastatic potential through mechanism(s) dependent on multiple circulating hemostatic system components, including prothrombin, platelets, fibrinogen and, more recently, fXIII. At least two of these circulating hemostatic factors (platelets and fibrinogen) have been shown to support metastatic potential by impeding the clearance of recently embolized tumor cells by natural killer (NK) cells. It is reasonable to hypothesize that tumor cell-associated TF expression also supports metastatic potential by a mechanism coupled to NK cell function. Here, we used C57BL/6-derived, Ras-transformed tumor cell lines expressing wildtype murine tissue factor (TFWT), a mutant TF lacking the intracytoplasmic portion (TFΔTail), or no tissue factor (TFO) to directly examine the interplay between tumor cell-associated TF and NK cell function in determining metastatic potential. Each of these cell lines was capable of robust, comparable tumor growth in wildtype C57BL/6 mice. Loss of either platelet function or fibrinogen significantly diminished the metastatic potential of TFWT cells, but this effect was entirely abrogated by the concomitant loss of NK cells. Similar results were obtained with TFΔTail cells, indicating that the cytoplasmic portion of TF is not critical to these interactions. To determine if the increase in metastatic potential conferred by tumor cell-associated TF expression is entirely linked to NK cell function, we compared the metastatic potential and early survival of TFWT and TFO cells in mice with and without NK cells. TFOcells rarely formed any visible metastatic foci in mice with intact NK cell function, while TFWT cells were aggressively metastatic. Importantly, TF expression remained a significant determinant of metastatic potential even in mice lacking NK cells. Comparisons of the early fate of TFWT and TFO cells revealed that TF expression was not a determinant of initial tumor cell localization within the lungs. Rather, TF expression supported the sustained adherence and/or survival of tumor cells. Taken together, these data indicate that one mechanism linking tumor cell-associated TF expression to metastatic potential is coupled to circulating hemostatic factors and results in impaired NK cell-mediated clearance of recently established micrometastatic foci. However, TF expression also supports metastasis by at least one additional mechanism that is independent of natural killer cell function.

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