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 Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

2018 ◽  
Author(s):  
Pil Soo Sung ◽  
Jeong Won Jang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Cell Therapies ◽  
Cell Dysfunction ◽  
Cell Functions

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

scholarly journals Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

2018 ◽  
Vol 19 (11) ◽  
pp. 3648 ◽  
Author(s):  
Pil Soo Sung ◽  
Jeong Won Jang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Cell Therapies ◽  
Cell Dysfunction ◽  
Cell Functions

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

scholarly journals Dysregulation of Natural Killer Cells in Obesity

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 573 ◽  
Author(s):  
Donal O’Shea ◽  
Andrew E. Hogan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Viral Infections ◽  
Nk Cell ◽  
Viral Immunity ◽  
Host Protection ◽  
Cell Functions ◽  
Innate Lymphocytes ◽  
The Impact

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity.

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 Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Margaret G. Lamb ◽  
Hemalatha G. Rangarajan ◽  
Brian P. Tullius ◽  
Dean A. Lee
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Cell Biology ◽  
Nk Cell ◽  
Killer Cell ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Wide Range

AbstractThe adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In the last 3 decades, NK cells have been utilized to harness the anti-tumor immune response in a wide range of malignancies, most notably with early evidence of efficacy in hematologic malignancies. NK cells are dysfunctional in patients with hematologic malignancies, and their number and function are further impaired by chemotherapy, radiation, and immunosuppressants used in initial therapy and hematopoietic stem cell transplantation. Restoring this innate immune deficit may lead to improved therapeutic outcomes. NK cell adoptive transfer has proven to be a safe in these settings, even in the setting of HLA mismatch, and a deeper understanding of NK cell biology and optimized expansion techniques have improved scalability and therapeutic efficacy. Here, we review the use of NK cell therapy in hematologic malignancies and discuss strategies to further improve the efficacy of NK cells against these diseases.

scholarly journals Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

2021 ◽  
Vol 8 ◽  
Author(s):  
William C. Kisseberth ◽  
Dean A. Lee
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Ex Vivo ◽  
Metastatic Cancer ◽  
Killer Cell ◽  
Therapeutic Interventions ◽  
Primary Bone Tumor ◽  
Cell Immunotherapy

Osteosarcoma is the most common primary bone tumor in both humans and dogs. It is a highly metastatic cancer and therapy has not improved significantly since the inclusion of adjuvant chemotherapy into disease treatment strategies. Osteosarcoma is an immunogenic tumor, and thus development of immunotherapies for its treatment, especially treatment of microscopic pulmonary metastases might improve outcomes. NK cells are lymphocytes of the innate immune system and can recognize a variety of stressed cells, including cancer cells, in the absence of major histocompatibility complex (MHC)-restricted receptor ligand interactions. NK cells have a role in controlling tumor progression and metastasis and are important mediators of different therapeutic interventions. The core hypothesis of adoptive natural killer (NK) cell therapy is there exists a natural defect in innate immunity (a combination of cancer-induced reduction in NK cell numbers and immunosuppressive mechanisms resulting in suppressed function) that can be restored by adoptive transfer of NK cells. Here, we review the rationale for adoptive NK cell immunotherapy, NK cell biology, TGFβ and the immunosuppressive microenvironment in osteosarcoma, manufacturing of ex vivo expanded NK cells for the dog and provide perspective on the present and future clinical applications of adoptive NK cell immunotherapy in spontaneous osteosarcoma and other cancers in the dog.

scholarly journals Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery

2021 ◽  
Vol 22 (21) ◽  
pp. 11378
Author(s):  
Marisa Market ◽  
Gayashan Tennakoon ◽  
Rebecca C. Auer
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Physiological Stress ◽  
Killer Cell ◽  
Surgical Removal ◽  
Surgical Trauma ◽  
Metastatic Recurrence ◽  
Cell Dysfunction ◽  
Inflammatory Phase

Surgical resection is the foundation for the curative treatment of solid tumors. However, metastatic recurrence due to the difficulty in eradicating micrometastases remain a feared outcome. Paradoxically, despite the beneficial effects of surgical removal of the primary tumor, the physiological stress resulting from surgical trauma serves to promote cancer recurrence and metastasis. The postoperative environment suppresses critical anti-tumor immune effector cells, including Natural Killer (NK) cells. The literature suggests that NK cells are critical mediators in the formation of metastases immediately following surgery. The following review will highlight the mechanisms that promote the formation of micrometastases by directly or indirectly inducing NK cell suppression following surgery. These include tissue hypoxia, neuroendocrine activation, hypercoagulation, the pro-inflammatory phase, and the anti-inflammatory phase. Perioperative therapeutic strategies designed to prevent or reverse NK cell dysfunction will also be examined for their potential to improve cancer outcomes by preventing surgery-induced metastases.

scholarly journals FAM13A regulates maturation and effector functions of natural killer cells

2020 ◽  
Author(s):  
Ni Zeng ◽  
Maud Theresine ◽  
Christophe Capelle ◽  
Neha Patil ◽  
Cécile Masquelier ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Lung Metastases ◽  
Sequence Similarity ◽  
Killer Cell ◽  
Cell Maturation ◽  
Chronic Obstructive ◽  
Effector Functions ◽  
Deficient Mice

AbstractThe education or licensing process is essentially required for the proper anti-tumor function of natural killer (NK) cells. Although several models for education have been proposed, the genetic factors regulating these processes still remain largely elusive. Here we show that FAM13A (family with sequence similarity 13, member A), strongly linked to the risk of prominent death-causing lung diseases, i.e., lung cancer and chronic obstructive pulmonary disease, critically modulated NK cell maturation and effector functions. Fam13a depletion promoted NK cell maturation, KLRG1 (killer cell lectin-like receptor G1) expression in NK cells and NK terminal differentiation in homeostatic mice. NK cells from Fam13a-deficient mice had impaired IFN-γ production and degranulation. Strikingly, the number of lung metastases induced by B16F10 melanoma cells was increased in Fam13a-deficient mice. Collectively, our data reveal a pivotal role of FAM13A in slowing down NK maturation, but promoting NK cell effector functions and immune protection against tumor metastasis.

scholarly journals Identification of Primary Natural Killer Cell Modulators by Chemical Library Screening with a Luciferase-Based Functional Assay

2018 ◽  
Vol 24 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Simon Hayek ◽  
Nassima Bekaddour ◽  
Laurie Besson ◽  
Rodolphe Alves de Sousa ◽  
Nicolas Pietrancosta ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
Target Cells ◽  
Functional Assay ◽  
Functional Screening ◽  
Cell Functions ◽  
Ifn Γ

Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings. Here we describe an efficient assay to measure the natural cytotoxicity of primary NK cells where the bioluminescent enzyme NanoLuc is constitutively expressed in the cytoplasm of target cells and is released in co-culture supernatants when lysis occurs. We fully characterized this assay using either purified NK cells or total peripheral blood mononuclear cells (PBMCs), including some patient samples, as effector cells. A pilot screen was also performed on a library of 782 metabolites, xenobiotics, and common drugs, which identified dextrometorphan and diphenhydramine as novel NK cell inhibitors. Finally, this assay was further improved by developing a dual-reporter cell line to simultaneously measure NK cell cytotoxicity and IFN-γ secretion in a single well, extending the potential of this system.

scholarly journals Macrophages induce natural killer cell dysfunction via KIR2DL1 during Echinococcus multilocularis infection

2021 ◽  
Vol 18 (7) ◽  
pp. 1527-1532
Author(s):  
Bayindala ◽  
Tuerganaili Aji ◽  
Bo Ran ◽  
Tieming Jiang ◽  
Wulan Tongbayier ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Echinococcus Multilocularis ◽  
Alveolar Echinococcosis ◽  
Nk Cell ◽  
Killer Cell ◽  
Parasitic Infection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Dysfunction ◽  
Elevated Expression

Purpose: To investigate the mechanism by which natural killer (NK) cells are compromised by infection with Echinococcus multilocularis in patients with alveolar echinococcosis (AE). Methods: NK cells from AE patients and healthy individuals were measured by flow cytometry and quantitative real-time polymerase chain reaction (PCR) to identify the frequency of different types of NK cells and assess their function. E. multilocularis cyst fluid (EMF) was applied to human monocytic leukaemia cells (THP-1 cells) to assess its effect on their differentiation. In a co-culture system with NK and EMF-THP-1 cells, the function of NK cells were analyzed by enzyme-linked immunosorbent assay (ELISA) with or without antibody against KIR2DL1. Results: Blood from AE patients had fewer CD56low NK cells (p < 0.01) with decreased production of IFN-γ and granzyme B due to the elevated expression of KIR2DL1 (p < 0.001). Treatment of THP-1 cells with EMF induced a tolerogenic phenotype upon activation. Incubation of these EMF-THP-1 cells with NK cells isolated from AE patients significantly impaired the cytotoxic function of NK cells, but this effect was largely blocked by an anti-KIR2DL1 antibody (p < 0.001). Conclusion: E. multilocularis modulates infection macrophages to induce NK cell dysfunction via interaction with KIR2DL1. These results provide a new insight into the mechanisms of parasitic infection-induced dysfunction of NK cells, and may be helpful for the development of therapeutic strategies for the treatment of alveolar echinococcosis.

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