Carfilzomib Enhances Natural Killer Cell-Mediated Lysis of Myeloma Linked with Decreasing Expression of HLA Class I

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1854-1854
Author(s):  
Jumei Shi ◽  
Guang Yang ◽  
Yuanyuan Kong ◽  
Minjie Gao ◽  
Yi Tao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Hematological Malignancies ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Dependent Manner ◽  
Down Regulation

Abstract Multiple myeloma (MM) is a malignant disorder characterized by uncontrolled monoclonal plasma cell proliferation. It accounts for 10% of all hematological malignancies and causes 15-20% of deaths from hematological malignancies. Although new therapies were introduced and overall survival of MM was improved in the last 10 years, MM still remains an incurable disease due to drug resistance. Natural killer (NK) cell-based treatments are promising therapies for multiple myeloma (MM). Carfilzomib (CFZ), a second-generation proteasome inhibitor, is used to treat patients with MM who are refractory or intolerant to both bortezomib and lenalidomide (or thalidomide). In this study, we determined that CFZ treatment enhanced the sensitivity of MM cells to NK cell-mediated lysis. Here, we report that CFZ decreased the expression of human leukocyte antigen (HLA) class I on MM cell lines and primary MM cells, the mean reduction was 47.7 ± 9.4% and 42.8 ± 12.4%, respectively. The down-regulation caused by CFZ occurred in a dose- and time- dependent manner. We compared the cell surface levels of HLA class I on MM cells in the presence or absence of CFZ after acid treatment. CFZ also down-regulated the expression of newly formed HLA class I on MM cells. CD107a expression levels were used to measure NK-cell degranulation. When NK cells were incubated with MM cells with CFZ treatment, the percentage of NK cells expressing CD107a on the surface greatly increased (mean ± SD: 33.6 ± 2.1%, for treated cells vs 16.7 ± 2.3%, for control cells, P < 0.05). We also showed that CFZ augmented NK-cell cytotoxity by a perforin/granzyme-mediated mechanism, because such enhancement was abolished when CMA, but not anti-TRAIL or anti-Fas-L antibodies, was added. Treatment of MM with CFZ significantly sensitized patients' MM cells to NK cell-mediated lysis (mean ± SD: 43.1 ± 6.4%, for treated cells vs 16.1 ± 4.0%, for control cells at effector/target (E/T) ratio of 10:1, n = 9, P < 0.01). Furthermore, the exogenous HLA-C binding peptides, used in the CFZ treated group rescued the down-regulation of HLA-C and reduced NK cell-mediated lysis to a similar level as in the untreated group. Blocking NKG2D, NCRs and TRAIL did not have a significant impact on NK cell lysis of myeloma cells. These implied the enhancement of NK cell-mediated lysis was mainly linked with the decreased expression of HLA class I. Our findings show a novel activity of CFZ as an immunomodulating agent and suggest a possible approach to therapeutically augment NK cell function in MM patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells

2018 ◽  
Vol 115 (15) ◽  
pp. E3509-E3518 ◽  
Author(s):  
Suresh Bugide ◽  
Michael R. Green ◽  
Narendra Wajapeyee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Down Regulation ◽  
Nkg2d Ligands ◽  
Enhancer Of Zeste

Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands. The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner. Collectively, these results demonstrate that EZH2 inhibition enhances HCC eradication by NK cells and that EZH2 functions, in part, as an oncogene by inhibiting immune response.

scholarly journals Evolution and Immunogenetics of Natural Killer Cell Receptors in Health and Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-25-SCI-25
Author(s):  
Peter Parham
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Mhc Class I Molecules ◽  
Kir Gene ◽  
Kir Haplotypes

Abstract Natural killer (NK) cells are phenotypically diverse lymphocytes that contribute to innate immunity, adaptive immunity and placental reproduction. Unlike B and T cells, NK cells do not use rearranging genes to make diverse antigen receptors that are clonally expressed. Instead, NK cells express diverse combinations of a variety of receptors that are encoded by conventional non-rearranging genes. Several of these receptors are specific for conserved and variable determinants of major histocompatibility complex (MHC) class I molecules. In humans, the killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of NK-cell receptors that recognize determinants of human leukocyte antigen (HLA)-A, B and C, the polymorphic human MHC class I molecules. HLA-A, B and C are the most polymorphic of human genes, and they correlate with susceptibility to a wide range of diseases and clinical outcomes, including allogeneic hematopoietic cell transplantation (HCT). During NK-cell development, interactions between epitopes of HLA class I and KIR educate the NK cells to recognize the normal expression of these epitopes on healthy cells, and to respond to unhealthy cells in which that expression is perturbed. In the context of HCT, certain types of HLA class I mismatch enable donor-derived NK cells to make an alloreactive and beneficial graft-versus-leukemia response. Although it is likely that all placental mammals have NK cells, only a small minority of these species has a diverse KIR family like that in humans. These comprise the simian primates: New World monkeys, Old World monkeys and the great apes. Under pressure from diverse and rapidly evolving pathogens, both the MHC class I and KIR gene families have been driven to evolve rapidly. Consequently, much of their character is species-specific. This is especially true for the human KIR gene family, which is qualitatively different from that of our closest relatives, the chimpanzees. Whereas chimpanzee KIR haplotype diversity represents variations on a theme of genes encoding robust MHC class I receptors, humans have an even balance between group A KIR haplotypes encoding robust HLA class I receptors and group B KIR haplotypes encoding receptors that, to varying degree, have been subject to natural selection for reduced functional recognition of HLA class I. A balance of A and B is present in all human populations and thus appears essential for the long-term survival and competitiveness of human communities. Whereas the A KIR haplotypes correlate with successful defense against viral infection, maternal B KIR haplotypes correlate with reproductive success and donor B KIR haplotypes improve the outcome of allogeneic HCT as therapy for acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Identification of Natural Killer Cell Receptor Phenotypes Associated with Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2997-2997
Author(s):  
Sonja J. Verheyden ◽  
Michel Bernier ◽  
Christian J. Demanet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Cell Receptor ◽  
Innate Immune ◽  
Class I ◽  
Leukemic Cells ◽  
Hla Class I Molecules

Abstract Introduction: Natural Killer (NK) cells play a key role in defense against tumor cells that have the capacity to downregulate Human Leukocyte Antigen (HLA) class I expression. It has been reported that leukemic cells can have down-regulated expression of HLA class I molecules. Apparently, the NK cells of these patients are not able to destroy these leukemic cells and may allow malignant cells to escape from innate immune control. This failure may be due to the fact that NK cells are part of the malignant clone and therefore might have a decreased function. An alternative hypothesis could be that these patients may display a NK cell Receptor (NKR) genotype incapable of destroying leukemic cells with aberrant expression of HLA class I molecules. The polymorphic nature of the NKR genes generates diverse repertoires in the human population, which display specificity in the innate immune response. Materials and Methods: In the present study, 11 Killer cell Immunoglobulin-like Receptor (KIRs) and 2 CD94/NKG2 receptors were genotyped by PCR-SSP in 96 leukemic patients and 148 healthy Caucasians. Results and Conclusion: We report a significant increased frequency of the more inhibitory AB KIR phenotype in leukemic patients compared to the controls (31.1% in healthy controls vs. 51.0% in leukemic patients, Pc = 0.002), which is related to the high prevalence of the inhibitory KIR2DL2 in this population (Pc = 0.007). Moreover, two specific KIR phenotypes AB1 and AB9, including all inhibitory KIRs, were significantly associated with leukemic patients. Our study suggests that an important percentage of leukemic patients express a KIR phenotype in favor of escape from NK cell immunity.

Natural Killer Cell Activities Against iPSCs-Derived HLA-Knockout Platelets and Megakaryocytes Reveal Perfect Rejection Profiles for Allotransfusion

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3841-3841 ◽  
Author(s):  
Daisuke Suzuki ◽  
Naoshi Sugimoto ◽  
Norihide Yoshikawa ◽  
Hiroshi Endo ◽  
Sou Nakamura ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Annexin V ◽  
Hla Class I ◽  
K562 Cells ◽  
Class I ◽  
Target Cells

Abstract Background Platelet transfusion refractoriness (PTR) due to immune factors occurs in 5-15% of thrombocytopenic patients who have received transfusions. The dominant cause of immune PTR is the production of allo-antibodies to human leukocyte antigen (HLA) class I, which is expressed on platelets. In current clinical settings, transfusion of HLA-compatible platelets is the only practical strategy, but their supply is weak due to limited donor source, gives excessive burden on specific donors, and requires increased efforts and costs. To overcome these issues, we plan to produce HLA-knockout platelets from iPSCs-derived megakaryocytes (MKs) as an alternative solution, applicable to all HLA types. However, whether they would be attacked by natural killer (NK) cells has not been well-studied. NK cells are known to show cytotoxic activity against cells downregulated for HLA class I ("missing self" theory). Therefore we assessed the interaction between HLA-knockout platelets derived from induced pluripotent stem cells (iPSCs) and NK cells in allogeneic settings. Methods and Results Immortalized megakaryocyte progenitor cell lines (imMKCLs) were previously established from iPSCs as a source of platelet production with a robust proliferation potential (Nakamura, 2014). Beta 2-microglobulin gene was knocked-out by CRISPR/Cas9 system to obtain HLA-knockout imMKCLs and platelets. NK cells were prepared from peripheral blood of eleven healthy donors. After co-cultures of NK cells and target cells for 6 hours with IL-2, we examined the NK cell cytolytic activity marker CD107, and target cell damage marker Annexin V using flow cytometry. Positive rates of both markers were not enhanced by co-culture with either HLA-expressed or HLA-knockout platelets for all donors. Furthermore, addition of platelets showed minimal effect on high cytotoxic activity of NK cells against K562 cells. In contrast, coculture of imMKCLs with NK cells resulted in higher detection of CD107 and Annexin V staining in some NK cell donors. These data suggested that platelets are immunologically inert for NK cells irrespective of class I HLA expression, while imMKCLs can be potentially attacked. Accordingly, platelets did not express NK cell activating ligands, which were expressed on imMKCLs and K562 cells. To confirm the above-mentioned results in vivo, mice were transfused with NK cells and platelets and MKs together. In our preliminary data, the circulation of platelets was not different between HLA-expressed or HLA-knockout type. In contrast, MKs were shown to be attacked in some cases. Conclusion HLA-knockout platelets evaded attacked from NK cells, while imMKCLs possessed immunogenicity to NK cells. This study provides extended experimental evidence that HLA-knockout platelets produced from a single imMKCL clone are immunologically applicable to all HLA types including majority of patients with PTR. On the other hand, contaminating imMKCLs in imMKCL-derived platelet products can be rejected by NK cells, contributing to their enhanced safety profiles. Taken together, stage of HLA-deficiency in imMKCLs as a starting material of platelet supply shall lead to industrial production of HLA universal platelets. Disclosures No relevant conflicts of interest to declare.

Decidual natural-killer-cell interaction with trophoblast: cytolysis or cytokine production?

2000 ◽  
Vol 28 (2) ◽  
pp. 196-198 ◽  
Author(s):  
Y. W. Loke ◽  
A. King
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Close Contact ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Hla Class I Antigens

At the implantation site, the uterine mucosa (decidua) is infiltrated by large numbers of natural killer (NK) cells. These NK cells are in close contact with the invading fetal trophoblast and we have proposed that they might be the effector cells that control the implantation of the allogeneic placenta. Recent characterization of NK cell receptors and their HLA class I ligands has suggested potential mechanisms by which NK cells might interact with trophoblast. However, what happens as a result of this interaction is not clear. The traditional method for investigating NK cell function in vitro is the protection from lysis of target cells by expression of HLA class I antigens. This might not be an accurate reflection of what happens in vivo. Another function of NK cells is the production of cytokines on contact with target cells. This could be an important outcome of the interaction between decidual NK cells and trophoblast. Decidual NK cells are known to produce a variety of cytokines; trophoblast cells express receptors for many of these cytokines, indicating that they can potentially respond. In this way, decidual NK cells have a significant influence on trophoblast behaviour during implantation.

scholarly journals Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function

2006 ◽  
Vol 203 (3) ◽  
pp. 633-645 ◽  
Author(s):  
Makoto Yawata ◽  
Nobuyo Yawata ◽  
Monia Draghi ◽  
Ann-Margaret Little ◽  
Fotini Partheniou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Cell Surface Expression ◽  
Cell Repertoire ◽  
Hla Polymorphism ◽  
Cellular Expression

Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand–receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR–HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population.

scholarly journals Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma

2021 ◽  
Vol 9 (7) ◽  
pp. e002958
Author(s):  
Haibo Sun ◽  
Thomas G Martin ◽  
John Marra ◽  
Denice Kong ◽  
Jonathon Keats ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Patient Specific ◽  
High Affinity ◽  
Genetic Makeup

BackgroundPhase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy.MethodsWe characterized 57 patients with RRMM receiving Isa-Len-Dex for polymorphisms of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigen (HLA) class I, and FCGR3A loci. In vitro ADCC assay, coincubating primary NK cells expressing specific KIR repertoire with multiple myeloma cell lines (MM cells) expressing selected HLA class I ligands, was used to confirm the identified genetic correlatives of clinical response.ResultsPatients with KIR3DL2+ and its cognate-ligand HLA-A3/11+ had superior PFS than patients missing this combination (HR=0.43; p=0.02), while patients carrying KIR2DL1+ and HLA-C2C2+ compared with to patients missing this pair showed short PFS (HR=3.54; p=0.05). Patients with KIR3DL2+ and HLA-A3/11+ plus high-affinity FCGR3A-158V allele showed the most prolonged PFS (HR=0.35; p=0.007). Consistent with these clinical data, mechanistic experiments demonstrated that NK cells expressing KIR3DL2 trigger greater ADCC when MM cells express HLA-A3/11. Inversely, NK cells expressing KIR2DL1 do not kill if MM cells express the HLA-C2C2 ligand. NK cells expressing high-affinity FCGR3A-158VV-induced greater ADCC compared with those with low-affinity FCGR3A-158FF.ConclusionsOur results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy.Trial registration numberNCT01749969.

scholarly journals Adaptive Admixture of HLA class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians

2021 ◽  
Author(s):  
Zhihui Deng ◽  
Jianxin Zhen ◽  
Genelle F Harrison ◽  
Guobin Zhang ◽  
Rui Chen ◽  
...  
Keyword(s):  
Natural Killer ◽  
High Frequency ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Telomeric Region ◽  
East Asians ◽  
Cell Functions ◽  
Specific Receptors

Abstract Human natural killer (NK) cells are essential for controlling infection, cancer and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B and -C genes, we show that the Chinese Southern Han are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the Chinese Southern Han KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B specific receptors. In all these characteristics, the Chinese Southern Han represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity and effector strength, likely augmenting resistance to endemic viral infections.

scholarly journals Natural Killer Cells in the Malignant Niche of Multiple Myeloma

2022 ◽  
Vol 12 ◽  
Author(s):  
Ondrej Venglar ◽  
Julio Rodriguez Bago ◽  
Benjamin Motais ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanisms ◽  
Hematological Malignancies ◽  
Cell Function ◽  
Nk Cell ◽  
Current Knowledge ◽  
Suppressor Activity ◽  
Infected Cells

Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.

HBV vaccination and HBV infection induces HBV-specific natural killer cell memory

Gut ◽  
2020 ◽  
pp. gutjnl-2019-319252 ◽  
Author(s):  
Ratna S Wijaya ◽  
Scott A Read ◽  
Naomi R Truong ◽  
Shuanglin Han ◽  
Dishen Chen ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Hbv Infection ◽  
Core Antigen ◽  
Dependent Manner ◽  
Antigen Specificity ◽  
Chronic Hbv

ObjectiveVaccination against hepatitis B virus (HBV) confers protection from subsequent infection through immunological memory that is traditionally considered the domain of the adaptive immune system. This view has been challenged following the identification of antigen-specific memory natural killer cells (mNKs) in mice and non-human primates. While the presence of mNKs has been suggested in humans based on the expansion of NK cells following pathogen exposure, evidence regarding antigen-specificity is lacking. Here, we demonstrate the existence of HBV-specific mNKs in humans after vaccination and in chronic HBV infection.DesignNK cell responses were evaluated by flow cytometry and ELISA following challenge with HBV antigens in HBV vaccinated, non-vaccinated and chronic HBV-infected individuals.ResultsNK cells from vaccinated subjects demonstrated higher cytotoxic and proliferative responses against autologous hepatitis B surface antigen (HBsAg)-pulsed monocyte-derived dendritic cells (moDCs) compared with unvaccinated subjects. Moreover, NK cell lysis of HBsAg-pulsed moDCs was significantly higher than that of hepatitis B core antigen (HBcAg)-pulsed moDCs (non-vaccine antigen) or tumour necrosis factor α-activated moDCs in a NKG2D-dependent manner. The mNKs response was mediated by CD56dim NK cells coexpressing CD57, CD69 and KLRG1. Further, mNKs from chronic hepatitis B patients exhibited greater degranulation against HBcAg-pulsed moDCs compared with unvaccinated or vaccinated patients. Notably, mNK activity was negatively correlated with HBV DNA levels.ConclusionsOur data support the presence of a mature mNKs following HBV antigen exposure either through vaccination or infection. Harnessing these antigen specific, functionally active mNKs provides an opportunity to develop novel treatments targeting HBV in chronic infection.

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