scholarly journals Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli

2020 ◽  
Author(s):  
Iñigo Terrén ◽  
Ane Orrantia ◽  
Alba Mosteiro ◽  
Joana Vitallé ◽  
Olatz Zenarruzabeitia ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Nk Cell ◽  
Cellular Functions ◽  
Effector Functions ◽  
Cytokine Stimulation ◽  
Cancer Immunotherapies ◽  
Cell Effector ◽  
Human Cytokine

ABSTRACTNatural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18. These IL-12/15/18-stimulated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have been revealed as a powerful tool in cancer immunotherapy due to their persistence in the host and their increased effector functions. Several studies have shown that NK cells modulate their metabolism in response to cytokine-stimulation and other stimuli, suggesting that there is a link between metabolism and cellular functions. In this paper, we have analyzed metabolic changes associated to IL-12/15/18-stimulation and the relevance of glycolytic pathway for NK cell effector functions. We have found that CIML NK cells are able to retain increased glycolytic machinery seven days after cytokine withdrawal. Furthermore, we found that glycolytic inhibition with 2-DG is stimuli-dependent and that differently affects to distinct effector functions. These findings may have implications in the design of NK cell-based cancer immunotherapies.

scholarly journals Metabolic changes of Interleukin-12/15/18-stimulated human NK cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iñigo Terrén ◽  
Ane Orrantia ◽  
Alba Mosteiro ◽  
Joana Vitallé ◽  
Olatz Zenarruzabeitia ◽  
...  
Keyword(s):  
Nk Cells ◽  
Metabolic Profile ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Interleukin 12 ◽  
Cellular Functions ◽  
Effector Functions ◽  
Cytokine Stimulation ◽  
Cancer Immunotherapies ◽  
Cell Effector

AbstractNatural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18. These IL-12/15/18-preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have been revealed as a powerful tool in cancer immunotherapy due to their persistence in the host and their increased effector functions. Several studies have shown that NK cells modulate their metabolism in response to cytokine-stimulation and other stimuli, suggesting that there is a link between metabolism and cellular functions. In this paper, we have analyzed metabolic changes associated to IL-12/15/18-stimulation and the relevance of glycolytic pathway for NK cell effector functions. We have found CIML NK cells are able to retain a metabolic profile shifted towards glycolysis seven days after cytokine withdrawal. Furthermore, we found that treatment with 2-DG differently affects distinct NK cell effector functions and is stimuli-dependent. These findings may have implications in the design of NK cell-based cancer immunotherapies.

scholarly journals The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 2 ◽  
Author(s):  
Marisa Market ◽  
Katherine Baxter ◽  
Leonard Angka ◽  
Michael Kennedy ◽  
Rebecca Auer
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Clonal Selection ◽  
Killer Cell ◽  
Cancer Recurrence ◽  
Effector Functions ◽  
Cell Dysfunction ◽  
Cell Functions

Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis.

scholarly journals Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuqing Cao ◽  
Xiaoyu Wang ◽  
Tianqiang Jin ◽  
Yu Tian ◽  
Chaoliu Dai ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Immune Checkpoint ◽  
Therapeutic Target ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Immune Checkpoint Molecules

Abstract Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

scholarly journals Activated Notch Supports Development of Cytokine Producing NK Cells Which Are Hyporesponsive and Fail to Acquire NK Cell Effector Functions

2009 ◽  
Vol 15 (2) ◽  
pp. 183-194 ◽  
Author(s):  
Veronika Bachanova ◽  
Valarie McCullar ◽  
Todd Lenvik ◽  
Rosanna Wangen ◽  
Karen A. Peterson ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Effector Functions ◽  
Cell Effector

scholarly journals Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Ahmet Yilmaz ◽  
Hanwei Cui ◽  
Michael A. Caligiuri ◽  
Jianhua Yu
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Comprehensive Overview ◽  
T Cell Therapy ◽  
Tumor Associated Antigens ◽  
Advantages And Disadvantages

AbstractNatural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of “off-the-shelf” anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors.

scholarly journals Natural Killer Cells in Cancer Immunotherapy

2019 ◽  
Vol 3 (1) ◽  
pp. 77-103 ◽  
Author(s):  
Jeffrey S. Miller ◽  
Lewis L. Lanier
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Nk Cell ◽  
Inhibitory Receptors ◽  
Antigen Specificity ◽  
Infected Cells ◽  
Missing Self ◽  
Fail Safe

Natural killer (NK) cells have evolved to complement T and B cells in host defense against pathogens and cancer. They recognize infected cells and tumors using a sophisticated array of activating, costimulatory, and inhibitory receptors that are expressed on NK cell subsets to create extensive functional diversity. NK cells can be targeted to kill with exquisite antigen specificity by antibody-dependent cellular cytotoxicity. NK and T cells share many of the costimulatory and inhibitory receptors that are currently under evaluation in the clinic for cancer immunotherapy. As with T cells, genetic engineering is being employed to modify NK cells to specifically target them to tumors and to enhance their effector functions. As the selective pressures exerted by immunotherapies to augment CD8+T cell responses may result in loss of MHC class I, NK cells may provide an important fail-safe to eliminate these tumors by their capacity to eliminate tumors that are “missing self.”

scholarly journals In Vivo Monitoring of Natural Killer Cell Trafficking during Tumor Immunotherapy

2014 ◽  
Vol 7 ◽  
pp. MRI.S13145 ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Samuel R. Barnes ◽  
Russell E. Jacobs
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Trafficking ◽  
Cancer Immunotherapies ◽  
Crucial Part

Natural killer (NK) cells are a crucial part of the innate immune system and play critical roles in host anti-viral, anti-microbial, and anti-tumor responses. The elucidation of NK cell biology and their therapeutic use are actively being pursued with 200 clinical trials currently underway. In this review, we outline the role of NK cells in cancer immunotherapies and summarize current noninvasive imaging technologies used to track NK cells in vivo to investigate mechanisms of action, develop new therapies, and evaluate efficacy of adoptive transfer.

scholarly journals Mast Cells and Natural Killer Cells—A Potentially Critical Interaction

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 514 ◽  
Author(s):  
Liliana Portales-Cervantes ◽  
Bassel Dawod ◽  
Jean S. Marshall
Keyword(s):  
Mast Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Host Defense ◽  
Cell Activation ◽  
Nk Cell ◽  
Mast Cell Activation ◽  
Target Cells ◽  
Effector Functions ◽  
Mucosal Surfaces

Natural killer (NK) cells play critical roles in host defense against infectious agents or neoplastic cells. NK cells provide a rapid innate immune response including the killing of target cells without the need for priming. However, activated NK cells can show improved effector functions. Mast cells are also critical for early host defense against a variety of pathogens and are predominately located at mucosal surfaces and close to blood vessels. Our group has recently shown that virus-infected mast cells selectively recruit NK cells and positively modulate their functions through mechanisms dependent on soluble mediators, such as interferons. Here, we review the possible consequences of this interaction in both host defense and pathologies involving NK cell and mast cell activation.

scholarly journals M144, a Murine Cytomegalovirus (Mcmv)-Encoded Major Histocompatibility Complex Class I Homologue, Confers Tumor Resistance to Natural Killer Cell–Mediated Rejection

1999 ◽  
Vol 190 (3) ◽  
pp. 435-444 ◽  
Author(s):  
Erika Cretney ◽  
Mariapia A. Degli-Esposti ◽  
Eloise H. Densley ◽  
Helen E. Farrell ◽  
Nick J. Davis-Poynter ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
Nk Cell ◽  
Effector Function ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Cell Effector Function ◽  
Cell Effector

Until now, it has been unclear whether murine cytomegalovirus (MCMV)-encoded protein m144 directly regulates natural killer (NK) cell effector function and whether the effects of m144 are only strictly evident in the context of MCMV infection. We have generated clones of the transporter associated with antigen processing (TAP)-2–deficient RMA-S T lymphoma cell line and its parent cell line, RMA, that stably express significant and equivalent levels of m144. In vivo NK cell–mediated rejection of RMA-S-m144 lymphomas was reduced compared with rejection of parental or mock-transfected RMA-S clones, indicating the ability of m144 to regulate NK cell–mediated responses in vivo. Significantly, the accumulation of NK cells in the peritoneum was reduced in mice challenged with RMA-S-m144, as was the lytic activity of NK cells recovered from the peritoneum. Expression of m144 on RMA-S cells also conferred resistance to cytotoxicity mediated in vitro by interleukin 2–activated adherent spleen NK cells. In summary, the data demonstrate that m144 confers some protection from NK cell effector function mediated in the absence of target cell class I expression, but that in vivo the major effect of m144 is to regulate NK cell accumulation and activation at the site of immune challenge.

scholarly journals CD16xCD33 Bispecific Killer Cell Engager (BiKE) as potential immunotherapeutic in pediatric patients with AML and biphenotypic ALL

2021 ◽  
Author(s):  
Sarah B. Reusing ◽  
Dan A. Vallera ◽  
Angela R. Manser ◽  
Titus Vatrin ◽  
Sanil Bhatia ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Killer Cell ◽  
Surface Expression ◽  
Hematopoietic Stem ◽  
Effector Functions ◽  
Promising Therapeutic Approach ◽  
Pediatric Aml ◽  
Cell Effector

AbstractSimilar to pediatric acute myeloid leukemia (AML) the subgroup of biphenotypic acute lymphoblastic leukemia (ALL) is a rare complex entity with adverse outcome, characterized by the surface expression of CD33. Despite novel and promising anti-CD19 targeted immunotherapies such as chimeric antigen receptor T cells and bispecific anti-CD19/CD3 antibodies, relapse and resistance remain a major challenge in about 30% to 60% of patients. To investigate the potential role of the fully humanized bispecific antibody CD16 × CD33 (BiKE) in children with CD33+ acute leukemia, we tested whether the reagent was able to boost NK cell effector functions against CD33+ AML and biphenotypic ALL blasts. Stimulation of primary NK cells from healthy volunteers with 16 × 33 BiKE led to increased cytotoxicity, degranulation and cytokine production against CD33+ cell lines. Moreover, BiKE treatment significantly increased degranulation, IFN-γ and TNF-α production against primary ALL and AML targets. Importantly, also NK cells from leukemic patients profited from restoration of effector functions by BiKE treatment, albeit to a lesser extent than NK cells from healthy donors. In particular, those patients with low perforin and granzyme expression showed compromised cytotoxic function even in the presence of BiKE. In patients with intrinsic NK cell deficiency, combination therapy of CD16xCD33 BiKE and allogeneic NK cells might thus be a promising therapeutic approach. Taken together, CD16xCD33 BiKE successfully increased NK cell effector functions against pediatric AML and biphenotypic ALL blasts and constitutes a promising new option for supporting maintenance therapy or “bridging” consolidation chemotherapy before hematopoietic stem cell transplantation.

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