Observation on the Efficacy of Consolidation Chemotherapy Combined with Allogeneic Natural Killer Cell Infusion in the Treatment of Low and Moderate Risk AML

Objective To evaluate the efficacy of consolidation chemotherapy combined with allogeneic natural killer (NK) cell infusion in the treatment of low or intermediate-risk(LIR) AML. Methods 23 cases of LIR AML patients with hematologic complete remission (CR) were enrolled from January 2014 to June 2019 and treated with mIL-21/4-1BBL actived NK cell transfusion combined with consolidation chemotherapy after 3 consolidation courses. Control group were concurrent patients from Department of Hematology and their gender, age, diagnosis, risk stratification of prognosis, CR and the number of courses of consolidate chemotherapy before NK cell transfusion were matched with LIR AML patients. Results A total of 45 times of NK cells were injected into 23 LIR AML patients during 4 to 7 courses of chemotherapy. The median NK cell infusion quantity was 7.5 (6.6~8.64) x 109/L, and the median survival rate of NK cells was 95.4 (93.9~96.9) %. Among them, the median CD3-CD56 + cell number is 5.0(1.4 ~ 6.4) × 109/L, which accounts for 76.8(30.8 ~ 82.9) %; The number of CD3+CD56+ cells was 0.55 (0.24~1.74) x 109/L, accounting for 8.8 (4.9~20.9) %. Before NK cell infusion, the number of patients with positive MRD in the treatment group was 9/23 (39.1%), and the control group was 19/46 (41.3%) (X2=0.03, P=0.862). After NK cell infusion, There was no significant difference in MRD that went from negative to positive between the treatment group and the control group(14.3%vs 22.2%, X2=0.037, P=0.847). In the treatment group, 66.7% (6/9) of the MRD were converted from positive to negative, which was significantly higher than that in the control group10.5% (2/19) (X2=6.811, P=0.009). Morphological recurrence occurred in 1 case of MRD negative in the treatment group and 2 cases of MRD positive in the control group. By the end of the follow-up, the median follow-up was 35 (10~59) months, the number of patients with morphological recurrence in the treatment group was 30.4% (7/23), which is significantly lower than that in the control group (50.2%, 24/46)(X2=2.929, P=0.087),although there was no statistically significant difference between the two groups. There was no significant difference on MRD-negative between the treatment group and the control group(43.5% vs 43.5%, X2=1.045, P=0.307).The 3-year leukemia -free survival were better in the treatment group(65.1±11.1)% than that in the control group (50.0±7.4)%(P=0.047). The 3year overall survival in the treatment and chemotherapy groups were(78.1±10.2)%and (65.8±8.0)%(P=0.212), respectively. Conclusion The consolidation of chemotherapy combined with allogeneic NK cell infusion contributes to the further remission of patients with LMR AML and the reduction of long-term recurrence. Figure Disclosures No relevant conflicts of interest to declare.

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Suppression of Natural Killer Cell Cytotoxicity in Postpartum Women

Biological Research For Nursing ◽

10.1177/1099800413498927 ◽

2013 ◽

Vol 16 (3) ◽

pp. 320-326 ◽

Cited By ~ 15

Author(s):

Maureen W. Groer ◽

Nagwa El-Badri ◽

Julie Djeu ◽

S. Nicole Williams ◽

Bradley Kane ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Postpartum Period ◽

Nk Cell ◽

Killer Cell ◽

Control Group ◽

Postpartum Women ◽

Cell Cytotoxicity ◽

Natural Killer Cell Cytotoxicity ◽

Nk Cytotoxicity

Little is known about the recovery of the immune system from normal pregnancy and whether the postpartum period is a uniquely adapted immune state. This report extends previous observations from our group of decreased natural killer (NK) cell cytotoxicity in the postpartum period. NK cytotoxicity was measured from 1 week through 9 months postpartum. In addition, NK cytotoxicity was assayed in the presence or absence of pooled plasmas collected from either postpartum or nonpostpartum women. Samples of cells were stained for inhibitory receptors and analyzed by flow cytometry. NK cytotoxicity remained decreased in postpartum women compared to controls through the first 6 postpartum months, returned to normal levels by 9 months, and remained normal at 12 months. NK cytotoxicity during the first 6 months was further inhibited by the addition of pooled plasma to NK cultures from postpartum women, but the addition of pooled plasma from the control group did not affect that group’s NK cultures. There were differences in inhibitory receptor staining between the two groups, with decreased CD158a and CD158b and increased NKG2A expression on postpartum NK cells during the first 3 postpartum months. These data suggest that NK cytotoxicity postpartum inhibition lasts 6 months and is influenced by unidentified postpartum plasma components. The effect may also involve receptors on NK cells.

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Effect of eccentric exercise on natural killer cell activity

Journal of Applied Physiology ◽

10.1152/jappl.1995.78.4.1442 ◽

1995 ◽

Vol 78 (4) ◽

pp. 1442-1446 ◽

Cited By ~ 15

Author(s):

J. Palmo ◽

S. Asp ◽

J. R. Daugaard ◽

E. A. Richter ◽

M. Klokker ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Eccentric Exercise ◽

Nk Cell ◽

Killer Cell ◽

Cell Activity ◽

Control Group ◽

Systemic Effects ◽

Nk Cell Activity ◽

Blood Samples

The effect of eccentric one-legged exercise on natural killer (NK) cell activity was studied in eight healthy males. To distinguish between local and systemic effects, blood samples were collected from veins in the exercising leg and resting arm. However, the results did not significantly differ between the leg and arm. To eliminate diurnal variations, the results were compared with a control group that did not exercise but had blood samples collected at the same time points. In the exercising group, plasma creatine kinase increased progressively during and up to 4 days after exercise. The percentage of CD16+ NK cells increased during exercise, which was paralleled by an increase in the NK cell activity per fixed number of blood mononuclear cells. The NK cell activity on a per NK cell basis did not change. The percentage of CD3+, CD4+, CD8+, CD19+, and CD14+ cells did not change significantly during exercise. The present study thus showed that eccentric exercise with a relatively small muscle mass (1 quadriceps femoris muscle) causes systemic effects on NK cells. It is suggested that the increase in plasma epinephrine during eccentric exercise is responsible for the observed increase in the percentage of CD16+ cells.

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The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding

Pathogens ◽

10.3390/pathogens10070866 ◽

2021 ◽

Vol 10 (7) ◽

pp. 866

Author(s):

Baca Chan ◽

Maja Arapović ◽

Laura Masters ◽

Francois Rwandamuiye ◽

Stipan Jonjić ◽

...

Keyword(s):

Nk Cells ◽

Salivary Glands ◽

Natural Killer ◽

Nk Cell ◽

Acute Infection ◽

Killer Cell ◽

Viral Escape ◽

Murine Cytomegalovirus ◽

Viral Shedding ◽

Cell Responses

As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.

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Natural Killer Cell Mobilization in Breast and Prostate Cancer Survivors: The Implications of Altered Stress Hormones Following Acute Exercise

Endocrines ◽

10.3390/endocrines2020012 ◽

2021 ◽

Vol 2 (2) ◽

pp. 121-132

Author(s):

Erik D. Hanson ◽

Lauren C. Bates ◽

Kaileigh Moertl ◽

Elizabeth S. Evans

Keyword(s):

Prostate Cancer ◽

Immune System ◽

Cancer Survivors ◽

Nk Cells ◽

Natural Killer ◽

Acute Exercise ◽

Nk Cell ◽

Killer Cell ◽

Current Evidence ◽

Cell Mobilization

Natural killer (NK) cells from the innate immune system are integral to overall immunity and also in managing the tumor burden during cancer. Breast (BCa) and prostate cancer (PCa) are the most common tumors in U.S. adults. Both BCa and PCa are frequently treated with hormone suppression therapies that are associated with numerous adverse effects including direct effects on the immune system. Regular exercise is recommended for cancer survivors to reduce side effects and improve quality of life. Acute exercise is a potent stimulus for NK cells in healthy individuals with current evidence indicating that NK mobilization in individuals with BCa and PCa is comparable. NK cell mobilization results from elevations in shear stress and catecholamine levels. Despite a normal NK cell response to exercise, increases in epinephrine are attenuated in BCa and PCa. The significance of this potential discrepancy still needs to be determined. However, alterations in adrenal hormone signaling are hypothesized to be due to chronic stress during cancer treatment. Additional compensatory factors induced by exercise are reviewed along with recommendations on standardized approaches to be used in exercise immunology studies involving oncology populations.

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Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Cancers ◽

10.3390/cancers13112796 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2796

Author(s):

Aicha E. Quamine ◽

Mallery R. Olsen ◽

Monica M. Cho ◽

Christian M. Capitini

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Solid Tumors ◽

Nk Cell ◽

Therapeutic Option ◽

Treatment Options ◽

Intensive Therapy ◽

Killer Cell ◽

Cell Therapies ◽

Pediatric Solid Tumors

Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

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Abstract WP319: miRNA Screening of Natural Killer Cell Identifies miR-1224 as a Post-Transcriptional Regulator of NK Cell Function After Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp319 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yan Feng ◽

Hui Zhao ◽

Fu-Dong Shi ◽

Weina Jin

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Nk Cells ◽

Expression Profile ◽

Mirna Expression ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Mirna Expression Profile ◽

Control Group

Objectives: To screen miRNA profile of peripheral NK cells in ischemic stroke mouse model and investigate a most promising candidate (miR-1224) for post-transcriptional regulation of NK cell function after ischemic stroke. Methods: Mice were subjected to a 60 min focal cerebral ischemia produced by transient intraluminal occlusion of MCAO. For NK cell isolation, cell suspensions from the spleens after reperfusion were enriched for NK cells using magnetic-bead sorting system after staining with anti-NK1.1 microbeads. The nCounter Mouse miRNA array was used to analyze miRNA expression profile in splenic NK cells over the time course of experimental ischemic stroke. Based on the miRNA data, we further in vitro modulated miR-1224 in NK cells using mimics or inhibitor, then injected i.v into Rag2-/-γc-/- recipient mice. Neurological function score was compared and spontaneous infection was assessed by pulmonary bacteria colony culture, and changes in potential signaling pathway (SP1/TNF-α) were verified by rt-PCR and western blot. Results: Through miRNA expression profile analysis, we have identified significant changes at each time point in peripheral NK cells after cerebral ischemia. Among all screened miRNA, miR-1224 remarkably increased in MCAO group, which was verified by PCR. Then isolated NK cells treated with mimics or inhibitors, were transferred to Rag2-/-γc-/- recipient mice. Compared with WT mice, Rag2-/-γc-/- mice with miR-1224 inhibitor exhibited increased NK cell number, enhanced NK cell activation/cytotoxicity feature, as well as better neurological behaviors and reduced pulmonary infection after MCAO. Moreover, compared with the control group, NK cells with miR-1224 inhibitor showed significantly increased SP1 gene and protein phosphorylation. As SP1 gene is one of the potential targets of miR-1224, this study suggests that miR-1224 may regulate NK cell function after MCAO, which is associated with SP1 pathway. Conclusion: The miRNA profiling of splenic NK cells provided insight into the functional mechanism and signaling pathways underlying the distinct organ-specific NK cell properties, which will contribute to the better understanding of NK cell mediated immune-response in relation to different stages of stroke.

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

Cancers ◽

10.3390/cancers11010002 ◽

2018 ◽

Vol 11 (1) ◽

pp. 2 ◽

Cited By ~ 7

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.

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Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

Journal of Translational Medicine ◽

10.1186/s12967-021-03203-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hee Young Na ◽

Yujun Park ◽

Soo Kyung Nam ◽

Jiwon Koh ◽

Yoonjin Kwak ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

B Cells ◽

Nk Cells ◽

Natural Killer ◽

Immune Cells ◽

Nk Cell ◽

Critical Role ◽

Killer Cell ◽

Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

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799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.799 ◽

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.

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Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?

Frontiers in Immunology ◽

10.3389/fimmu.2021.616853 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elena Gianchecchi ◽

Domenico V. Delfino ◽

Alessandra Fierabracci

Keyword(s):

Systemic Sclerosis ◽

Autoimmune Diseases ◽

Cytotoxic Activity ◽

Nk Cells ◽

Natural Killer ◽

T Cell Activation ◽

Cell Activation ◽

Nk Cell ◽

Killer Cell

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

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