Hepatocellular carcinoma (HCC) is well characterized as a heterogeneous disease. Its late-stage diagnosis and chemotherapy resistance make it one of the refractory tumors in China. Natural killer (NK) cells play a significant role in immune surveillance. However, NK cells become dysfunctional in the progression of HCC, leading to tumor immune escape. This article reviews the recent progress on different strategies of NK cell-based immunotherapy in treating HCC, including direct adoptive NK cell transfer, gene engineering in NK cell, NK cell receptor targeting, immunosuppressive microenvironment modification, and tumor toxicity enhancement by cytokines or traditional Chinese medicine. These NK cell-based strategies have shown promising therapeutic potential.
Humans ; Carcinoma, Hepatocellular/therapy* ; Liver Neoplasms/therapy* ; Immunotherapy ; Killer Cells, Natural ; Receptors, Natural Killer Cell ; Tumor Microenvironment

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection. However, it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer (NK) cell response in people living with human immunodeficiency virus (PLWH) and healthy individuals. METHODS: Forty-seven PLWH and thirty healthy controls (HCs) inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study. The effect of SARS-CoV-2 vaccine on NK cell frequency, phenotype, and function in PLWH and HCs was evaluated by flow cytometry, and the response of NK cells to SARS-CoV-2 Omicron Spike (SARS-2-OS) protein stimulation was also evaluated. RESULTS: SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH, which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine. However, in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers. Additionally, the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0, 4 and 12 weeks, but the percentage of CD16 + NK cells in PLWH was significantly higher than that in HCs at 2, 4 and 12 weeks after the third dose of vaccine. Interestingly, the frequency of CD16 + NK cells was significantly negatively correlated with the proportion of CD107a + NK cells in PLWH at each time point after the third dose. Similarly, this phenomenon was also observed in HCs at 0, 2, and 4 weeks after the third dose. Finally, regardless of whether NK cells were stimulated with SARS-2-OS or not, we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs. CONCLUSION s:SARS-CoV-2 vaccine elicited activation and degranulation of NK cells, indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell immune response.
Humans ; COVID-19 Vaccines/therapeutic use* ; COVID-19 ; SARS-CoV-2 ; Killer Cells, Natural ; HIV Infections ; Antibodies, Viral

Objective To identify the sets of lymphocytes that could systematically evaluate immune function of colorectal cancer patients, based on the expression of colorectal cancer T cells, natural killer (NK) cells, and NKT cell surface protein receptors. Methods Peripheral blood samples from 144 patients with colorectal cancer and 87 healthy controls were collected, and the differences in surface receptors of lymphocyte subsets in peripheral blood of patients and healthy controls were analyzed by means of flow cytometry and cell culture. Results Compared with healthy control group, the percentage of peripheral blood total lymphocytes, CD16^brightCD56^dimNK cells and NKT cells decreased in patients with colorectal cancer. The percentage of T cells, CD16^brightCD56^dimNK cells and NKT cell surface inhibitory receptors T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) increased; T cells, NK cells, NKT cell surface chemokine receptor C-C motif chemokine receptor 7 (CCR7) slightly decreased. Conclusion There are differences in the proportion of NK cell subsets and the expression profile of surface receptors in peripheral blood of patients with colorectal cancer.
Humans ; Lymphocyte Subsets ; Killer Cells, Natural ; Lymphocyte Count ; Receptors, Chemokine ; Colorectal Neoplasms

CD226 is an activated receptor on the surface of natural killer (NK) cells. It competes with TIGIT and CD96 to bind to ligands such as CD155 on the surface of tumor cells and mediates the killing function of NK cells. Although TIGIT and CD96 have other binding ligands in the tumor microenvironment, they compete to bind CD115 ligands with higher affinity and inhibit the activity of NK cells, which allows tumor cells to evade killing. Therefore, studying the expression patterns of these three NK cell surface receptors in different tumors and monitoring their binding ability with ligands will help us to explore new tumor treatment strategies. This article reviews the role and mechanism of CD226, TIGIT, CD96 and other NK cell receptor molecules in regulating NK cell function in anti-tumor immune response.
Ligands ; Receptors, Immunologic ; Receptors, Natural Killer Cell ; Killer Cells, Natural ; Antigens, CD

Natural killer (NK) cells are an important part of the body's innate immune system. As the first line of defense against pathogens, they need to be transformed into a mature state under the control of various cell signaling molecules and transcription factors to play cytotoxic and immune regulatory roles. Under the interaction of activated receptors and inhibitory receptors, NK cells are activated to perform a direct cell killing effect by secreting perforin and granzyme, or indirectly eliminate pathogenic microorganisms in the body by secreting various cytokines, such as type I and type II interferons. These functions of NK cells play a very important role in antiviral and anti-autoimmune diseases, especially in anti-tumor.
Humans ; Killer Cells, Natural ; Interferon-gamma ; Apoptosis ; Autoimmune Diseases ; Cytokines

Chimeric Antigen Receptor (CAR) is a research hotspot in the field of cellular immunotherapy in recent years, and CAR-T cells therapy are developing rapidly in hematological malignant tumors, but their clinical application is still limited by related risks. It is particularly important to find more optimized immunoreactive cells. Natural killer (NK) cells, as key effector cells of innate immunity, can kill tumor or infected cells quickly without prior sensitization. Autologous or allogeneic NK cell infusion has become an effective cell therapy for acute myeloid leukemia (AML). CAR-NK cells combine the advantages of CAR targeting tumor specific antigens and enhancing immune cells activity with the innate antitumor function of NK cells to enhance the targeting and lytic activity of NK cells to AML primordial cells. At present, most of the CAR-NK treatments for AML are still in the stage of specific target screening and verification. This article reviews the latest research progress of CAR-NK cell therapy in the field of AML therapy.
Humans ; Receptors, Chimeric Antigen ; Killer Cells, Natural ; Leukemia, Myeloid, Acute/drug therapy* ; Immunotherapy, Adoptive ; Immunotherapy

OBJECTIVE: Aconite is a traditional Chinese herbal medicine that has been found to inhibit the development of liver cancer; however, its exact molecular mechanisms in this process remain unclear. This study explores how aconite aqueous extract (AAE) inhibits hepatocellular carcinoma (HCC). METHODS: An in vivo mouse model of subcutaneous liver cancer was established. After AAE treatment, immunohistochemistry (IHC) was used to determine the effect of AAE on natural killer (NK) cells. Subsequently, C57BL/6 mice were used to establish the subcutaneous tumor model, and a group of these mice were treated with anti-PK163 antibody to remove NK cells, which was verified by flow cytometry and IHC. The effect of AAE on the proliferation of HCC cells in vitro was determined using cell counting kit-8. The effect of AAE on chemokine production in HCC cells was measured using real-time quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay. The effect of AAE on the migration of NK cells was determined using a transwell assay. Finally, the molecular mechanism was investigated using the Western blotting method. RESULTS: We demonstrated that the ability of AAE to induce overexpression of the cytokine C-C motif chemokine ligand 2 (CCL2) in HCC cells is fundamental to the infiltration of NK cells into the tumor bed. Mechanistically, we found that the upregulation of CCL2 was achieved by the activation of c-Jun N-terminal kinase but not extracellular regulated protein kinase or p38. CONCLUSION Our findings suggest that AAE can be used as an effective immune adjuvant to enhance antitumor immunity by increasing NK cell infiltration into tumors, which could help to improve the efficacy of HCC treatments. Please cite this article as: Yang KD, Zhang X, Shao MC, Wang LN. Aconite aqueous extract inhibits the growth of hepatocellular carcinoma through CCL2-dependent enhancement of natural killer cell infiltration. J Integr Med. 2023; 21(6): 575-583.
Animals ; Mice ; Carcinoma, Hepatocellular/drug therapy* ; Liver Neoplasms/drug therapy* ; Aconitum ; Ligands ; Mice, Inbred C57BL ; Killer Cells, Natural/metabolism* ; Chemokines/pharmacology* ; Cell Line, Tumor

Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical "live" drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of "off-the-shelf" strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.
Humans ; Receptors, Chimeric Antigen/genetics* ; Induced Pluripotent Stem Cells ; Killer Cells, Natural ; Cell- and Tissue-Based Therapy ; T-Lymphocytes ; Immunotherapy, Adoptive ; Neoplasms/genetics*

OBJECTIVES: To study the clinical features of children with coronavirus disease 2019 (COVID-19) caused by Delta variant infection in different ages groups. METHODS: A total of 45 children with COVID-19 caused by Delta variant infection who were hospitalized in the designated hospital in Henan Province, China, from November 17 to December 17, 2021, were included. They were divided into three groups: <6 years group (n=16), 6-13 years group (n=16), and >13 years group (n=13). The three groups were compared in clinical features and laboratory examination data. RESULTS: COVID-19 in all age groups was mainly mild. Main manifestations included cough and expectoration in the three groups, and fever was only observed in the 6-13 years group. The <6 years group had significantly higher serum levels of aspartate aminotransferase, lactate dehydrogenase, and creatine kinase isoenzymes than the other two groups (P<0.05). The 6-13 years group had the highest proportion of children with elevated serum creatinine levels (50%). Among the three groups, only 4 children in the >13 years group had an increase in serum C-reactive protein levels. The 6-13 years group had the lowest counts of CD3⁺CD4⁺ lymphocytes, CD3⁺CD8⁺ lymphocytes, and natural killer cells in the peripheral blood among the three groups. The >13 years group had a significantly higher positive rate of SARS-CoV-2 IgG on admission than the other two groups (P<0.05). There was no significant difference in the imaging findings on chest CT among the three groups (P>0.05). CONCLUSIONS The clinical features of COVID-19 caused by Delta variant infection in children of different age groups may be different: children aged <6 years tend to develop myocardial injury, and those aged 6-13 years have fever except cough and expectoration and tend to develop renal and immune dysfunction.
Humans ; Child ; COVID-19 ; SARS-CoV-2 ; Cough/etiology* ; Killer Cells, Natural ; China/epidemiology* ; Fever ; Retrospective Studies

Although the development of novel drugs has significantly improved the survival of patients with multiple myeloma (MM) over the past decades,the lack of effective therapeutic options for relapsed and refractory MM results in poor prognosis.The chimeric antigen receptor (CAR) T-cell therapy has achieved considerable progress in relapsed and refractory MM.Nevertheless,this therapy still has limitations such as cytokine release syndrome,neurotoxicity,and off-target effects.Natural killer (NK) cells,as a critical component of the innate immune system,play an essential role in tumor immunosurveillance.Therefore,CAR-modified NK (CAR-NK) cells are put forward as a therapeutic option for MM.The available studies have suggested that multiple targets can be used as specific therapeutic targets for CAR-NK cell therapy and confirmed their antitumor effects in MM cell lines and animal models.This review summarizes the anti-tumor mechanisms,biological characteristics,and dysfunction of NK cells in the MM tumor microenvironment,as well as the basic and clinical research progress of CAR-NK cells in treating MM.
Animals ; Receptors, Chimeric Antigen/metabolism* ; Multiple Myeloma/metabolism* ; Killer Cells, Natural/metabolism* ; Immunotherapy, Adoptive/methods* ; Tumor Microenvironment