scholarly journals The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

2021 ◽  
Vol 28 (2) ◽  
pp. 1077-1093
Author(s):  
Synat Kang ◽  
Xuefeng Gao ◽  
Li Zhang ◽  
Erna Yang ◽  
Yonghui Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Tumor Development ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Clinical Applications ◽  
Therapeutic Approaches ◽  
Leukocyte Antigens ◽  
Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

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.

Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3624-3631 ◽  
Author(s):  
Mónica Gumá ◽  
Matthias Budt ◽  
Andrea Sáez ◽  
Tamara Brckalo ◽  
Hartmut Hengel ◽  
...  
Keyword(s):  
Nk Cells ◽  
Human Cytomegalovirus ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Receptor ◽  
Peripheral Blood Lymphocytes ◽  
Leukocyte Antigen ◽  
Receptor Repertoire ◽  
Infected Cells

CD94/NKG2C+ natural killer (NK) cells are increased in healthy individuals infected with human cytomegalovirus (HCMV), suggesting that HCMV infection may shape the NK cell receptor repertoire. To address this question, we analyzed the distribution of NK cell subsets in peripheral blood lymphocytes (PBLs) cocultured with HCMV-infected fibroblasts. A substantial increase of NK cells was detected by day 10 in samples from a group of HCMV+ donors, and CD94/NKG2C+ cells outnumbered the CD94/NKG2A+ subset. Fibroblast infection was required to induce the preferential expansion of CD94/NKG2C+ NK cells that was comparable with allogeneic or autologous fibroblasts, and different virus strains. A CD94-specific monoclonal antibody (mAb) abrogated the effect, supporting an involvement of the lectinlike receptor. Purified CD56+ populations stimulated with HCMV-infected cells did not proliferate, but the expansion of the CD94/NKG2C+ subset was detected in the presence of interleukin-15 (IL-15). Experiments with HCMV deletion mutants indicated that the response of CD94/NKG2C+ NK cells was independent of the UL16, UL18, and UL40 HCMV genes, but was impaired when cells were infected with a mutant lacking the US2-11 gene region. Taken together the data support that the interaction of CD94/NKG2C with HCMV-infected fibroblasts, concomitant to the inhibition of human leukocyte antigen (HLA) class I expression, promotes an outgrowth of CD94/NKG2C+ NK cells.

scholarly journals Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 769 ◽  
Author(s):  
Kyle B. Lupo ◽  
Sandro Matosevic
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Published Evidence

Natural killer (NK) cells are attractive within adoptive transfer settings in cancer immunotherapy due to their potential for allogeneic use; their alloreactivity is enhanced under conditions of killer immunoglobulin-like receptor (KIR) mismatch with human leukocyte antigen (HLA) ligands on cancer cells. In addition to this, NK cells are platforms for genetic modification, and proliferate in vivo for a shorter time relative to T cells, limiting off-target activation. Current clinical studies have demonstrated the safety and efficacy of allogeneic NK cell adoptive transfer therapies as a means for treatment of hematologic malignancies and, to a lesser extent, solid tumors. However, challenges associated with sourcing allogeneic NK cells have given rise to controversy over the contribution of NK cells to graft-versus-host disease (GvHD). Specifically, blood-derived NK cell infusions contain contaminating T cells, whose activation with NK-stimulating cytokines has been known to lead to heightened release of proinflammatory cytokines and trigger the onset of GvHD in vivo. NK cells sourced from cell lines and stem cells lack contaminating T cells, but can also lack many phenotypic characteristics of mature NK cells. Here, we discuss the available published evidence for the varying roles of NK cells in GvHD and, more broadly, their use in allogeneic adoptive transfer settings to treat various cancers.

scholarly journals NKG2A Complexed with CD94 Defines a Novel Inhibitory Natural Killer Cell Receptor

1997 ◽  
Vol 185 (4) ◽  
pp. 795-800 ◽  
Author(s):  
Andrew G. Brooks ◽  
Phillip E. Posch ◽  
Christopher J. Scorzelli ◽  
Francisco Borrego ◽  
John E. Coligan
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Protein S ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Cell Clones

CD94 is a C-type lectin expressed by natural killer (NK) cells and a subset of T cells. Blocking studies using anti-CD94 mAbs have suggested that it is a receptor for human leukocyte antigen class I molecules. CD94 has recently been shown to be a 26-kD protein covalently associated with an unidentified 43-kD protein(s). This report shows that NKG2A, a 43-kD protein, is covalently associated with CD94 on the surface of NK cells. Cell surface expression of NKG2A is dependent on the association with CD94 as glycosylation patterns characteristic of mature proteins are found only in NKG2A that is associated with CD94. Analysis of NK cell clones showed that NKG2A was expressed in all NK cell clones whose CD16-dependent killing was inhibited by cross-linking CD94. The induction of an inhibitory signal is consistent with the presence of two immunoreceptor tyrosine-based inhibitory motifs (V/LXYXXL) on the cytoplasmic domain of NKG2A. Similar motifs are found on Ly49 and killer cell inhibitory receptors, which also transmit negative signals to NK cells.

scholarly journals A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 174-193
Author(s):  
Jenny Valentina Garmendia ◽  
Juan Bautista De Sanctis
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Embryo Implantation ◽  
Inflammatory Cells ◽  
Cell Physiology ◽  
Therapeutic Approaches ◽  
Pharmacological Modulation ◽  
New Therapeutic Approaches ◽  
Pharmacologic Modulation ◽  
Inflammatory Burden

NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology.

scholarly journals Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 525
Author(s):  
Kwang-Soo Kim ◽  
Dong-Hwan Kim ◽  
Dong-Hyun Kim
Keyword(s):  
Clinical Trials ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Therapeutic Efficacy ◽  
Nk Cell ◽  
Cell Cancer ◽  
Immune Surveillance ◽  
Cytolytic Activity ◽  
Contact Frequency

Among various immunotherapies, natural killer (NK) cell cancer immunotherapy using adoptive transfer of NK cells takes a unique position by targeting tumor cells that evade the host immune surveillance. As the first-line innate effector cell, it has been revealed that NK cells have distinct mechanisms to both eliminate cancer cells directly and amplify the anticancer immune system. Over the last 40 years, NK cell cancer immunotherapy has shown encouraging reports in pre-clinic and clinic settings. In total, 288 clinical trials are investigating various NK cell immunotherapies to treat hematologic and solid malignancies in 2021. However, the clinical outcomes are unsatisfying, with remained challenges. The major limitation is attributed to the immune-suppressive tumor microenvironment (TME), low activity of NK cells, inadequate homing of NK cells, and limited contact frequency of NK cells with tumor cells. Innovative strategies to promote the cytolytic activity, durable persistence, activation, and tumor-infiltration of NK cells are required to advance NK cell cancer immunotherapy. As maturing nanotechnology and nanomedicine for clinical applications, there is a greater opportunity to augment NK cell therapeutic efficacy for the treatment of cancers. Active molecules/cytokine delivery, imaging, and physicochemical properties of nanoparticles are well equipped to overcome the challenges of NK cell cancer immunotherapy. Here, we discuss recent clinical trials of NK cell cancer immunotherapy, NK cell cancer immunotherapy challenges, and advances of nanoparticle-mediated NK cell therapeutic efficacy augmentation.

scholarly journals Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 298
Author(s):  
Arnika K. Wagner ◽  
Ulf Gehrmann ◽  
Stefanie Hiltbrunner ◽  
Valentina Carannante ◽  
Thuy T. Luu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Mouse Strains ◽  
Target Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Missing Self

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to α-galactosylceramide (αGC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with αGC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that αGC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding αGC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests αGC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response.

scholarly journals Cancer exosomes and natural killer cells dysfunction: biological roles, clinical significance and implications for immunotherapy

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Reza Hosseini ◽  
Hamzeh Sarvnaz ◽  
Maedeh Arabpour ◽  
Samira Molaei Ramshe ◽  
Leila Asef-Kabiri ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Clinical Significance ◽  
Surveillance System ◽  
Cancer Biology ◽  
Nk Cell ◽  
Ex Vivo ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Cell Responses

AbstractTumor-derived exosomes (TDEs) play pivotal roles in several aspects of cancer biology. It is now evident that TDEs also favor tumor growth by negatively affecting anti-tumor immunity. As important sentinels of immune surveillance system, natural killer (NK) cells can recognize malignant cells very early and counteract the tumor development and metastasis without a need for additional activation. Based on this rationale, adoptive transfer of ex vivo expanded NK cells/NK cell lines, such as NK-92 cells, has attracted great attention and is widely studied as a promising immunotherapy for cancer treatment. However, by exploiting various strategies, including secretion of exosomes, cancer cells are able to subvert NK cell responses. This paper reviews the roles of TDEs in cancer-induced NK cells impairments with mechanistic insights. The clinical significance and potential approaches to nullify the effects of TDEs on NK cells in cancer immunotherapy are also discussed.

scholarly journals NK Cell-Based Immunotherapy and Therapeutic Perspective in Gliomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Changqing Pan ◽  
You Zhai ◽  
Guanzhang Li ◽  
Tao Jiang ◽  
Wei Zhang
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Primary Brain Tumor ◽  
Therapeutic Approaches ◽  
Independent Manner ◽  
Clinical Prognosis ◽  
Cell Based Therapy ◽  
Current Therapies ◽  
Immunosuppressive Microenvironment ◽  
Therapeutic Perspective

Glioma is the most common malignant primary brain tumor diagnosed in adults. Current therapies are unable to improve its clinical prognosis, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor and its immunosuppressive microenvironment. Development of new therapies that avoid this immune evasion could improve the response to the current treatments. Natural killer (NK) cells are an intriguing candidate for the next wave of therapies because of several unique features that they possess. For example, NK cell-based immunotherapy causes minimal graft-versus-host disease. Cytokine release syndrome is less likely to occur during chimeric antigen receptor (CAR)-NK therapy, and CAR-NK cells can kill targets in a CAR-independent manner. However, NK cell-based therapy in treating glioma faces several difficulties. For example, CAR molecules are not sufficiently well designed so that they will thoroughly release functioning NK cells. Compared to hematological malignancies, the application of many potential NK cell-based therapies in glioma lags far behind. Here, we review several issues of NK cells and propose several strategies that will improve the efficacy of NK cell-based cancer immunotherapy in the treatment of glioma.

scholarly journals NEPdb: A Database of T-Cell Experimentally-Validated Neoantigens and Pan-Cancer Predicted Neoepitopes for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiaqi Xia ◽  
Peng Bai ◽  
Weiliang Fan ◽  
Qiming Li ◽  
Yongzheng Li ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Somatic Mutations ◽  
Tumor Regression ◽  
Human Leukocyte ◽  
T Cell Recognition ◽  
Leukocyte Antigens ◽  
Pan Cancer ◽  
Automatic Pipeline ◽  
Cancer Studies

T-cell recognition of somatic mutation-derived cancer neoepitopes can lead to tumor regression. Due to the difficulty to identify effective neoepitopes, constructing a database for sharing experimentally validated cancer neoantigens will be beneficial to precise cancer immunotherapy. Meanwhile, the routine neoepitope prediction in silico is important but laborious for clinical use. Here we present NEPdb, a database that contains more than 17,000 validated human immunogenic neoantigens and ineffective neoepitopes within human leukocyte antigens (HLAs) via curating published literature with our semi-automatic pipeline. Furthermore, NEPdb also provides pan-cancer level predicted HLA-I neoepitopes derived from 16,745 shared cancer somatic mutations, using state-of-the-art predictors. With a well-designed search engine and visualization modes, this database would enhance the efficiency of neoantigen-based cancer studies and treatments. NEPdb is freely available at http://nep.whu.edu.cn/.

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