Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies

Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

茵达日-4通过调节肠道菌群和血清素水平缓解肠易激综合征大鼠的内脏超敏反应

[目的]本研究旨在评估茵达日-4在大鼠动物模型中改善IBS症状的功效,并探究茵达日-4对如肠组织血清素水平和肠道菌群结构及组成等IBS潜在治疗靶点的影响。[方法]通过母子分离,醋酸灌肠和束缚应急复合造模方法构建IBS大鼠模型,利用茵达日-4水提物进行灌胃干预10天后,分析并比较对照组、模型组和干预组大鼠粪便含水量、内脏敏感性、肠道菌群和肠组织血清素水平等指标。[结果]茵达日-4干预可剂量依赖地逆转IBS模型鼠内脏超敏反应症状。其缓解内脏超敏反应的效果与肠道菌群结构和组成的调节,以及结肠中血清素水平异常升高的回调相关。茵达日-4治疗后结肠血清素水平的降低可能与Helicobacter属菌丰度的降低和Butyricimonas属菌的富集有关。[结论]茵达日-4对IBS模型鼠内脏超敏反应具有显著治疗效果。茵达日-4对肠道菌群和结肠中血清素水平的调节在模型鼠IBS症状缓解过程中发挥作用。

Natural Killer Cell-Based Immunotherapy for Cancer: Advances and Prospects

Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," recognize abnormal cells, and eliminate transformed cells and malignancies in real time, tumors develop several strategies to escape from NK cell attack. These strategies include upregulating ligands for the inhibitory receptors of NK cells and producing soluble molecules or immunosuppressive factors. Various types of NK cells are currently being applied in clinical trials, including autologous or allogeneic NK cells, umbilical cord blood (UCB) or induced pluripotent stem cell (iPSC)-derived NK cells, memory-like NK cells, and NK cell line NK-92 cells, for the treatment of different types of tumors. Chimeric antigen receptors (CARs)-NK cells have recently shown great potential due to their redirect specificity and effective antitumor activity. In this review, we summarize the mechanisms of tumor escape from NK cell recognition, the current status and advanced progress of NK cell-based immunotherapy, ways of enhancing the antitumor capacity of NK cells in vivo, and major challenges for clinical practice in this field.

Holistic Service-Based Architecture for Space-Air-Ground Integrated Network for 5G-Advanced and Beyond

The Service-based Architecture(SBA) is one of the key innovations of 5G architecture that leverage modularized, self-contained and independent services to provide flexible and cloud-native 5G network. In this paper, SBA for Space-Air-Ground Integrated Network(SAGIN) is investigated to enable the 5G integration deployment. This paper proposes a novel Holistic Service-based Architecture(H-SBA)for SAGIN of 5G-Advanced and beyond, i.e., 6G. The H-SBA introduces the concept of end-to-end servicebased architecture design. The "Network Function Service", introduced in 5G SBA, is extended from Control Plane to User Plane, from core network to access network. Based on H-SBA, the new generation of protocol design is proposed, which proposes to use IETF QUIC and SRv6 to substitute 5G HTTP/2.0 and GTP-U. Testing results show that new protocols can achieve low latency and high throughput, making them promising candidate for H-SBA.

Special Issue on Machine Fault Diagnostics and Prognostics

Machine components and systems, such as gears, bearings, pipes, cutting tools and turbines, may experience various types of faults, such as breakage, crack, pitting, wear, corrosion. If not being properly monitored and treated, such faults can propagate and lead to machinery perfor- mance degradation, malfunction, or even severe compo- nent/system failure. It is significant to reliably detect machinery defects, evaluate their severity, predict the fault propagation trends, and schedule optimized maintenance and inspection activities to prevent unexpected failures. Advances in these areas will support ensuring equipment and production reliability, safety, quality and productivity.

Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing

Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK cells are not well defined.Hepatocellular carcinoma(HCC)accounts for approximately 80%of primary liver cancer worldwide,yet the biological characteristics of NK cells in the HCC environment are unclear.Therefore,we aimed to determine these cells’roles in tumorigenesis and prognosis.Methods:We compared the single-cell RNA sequencing profiles of NK cells purified from blood(n=1),healthy liver tissues(n=3),HCC tumor tissues(n=4),and peritumor liver tissues(n=1)to identify NK cell subsets.Furthermore,we performed bioinformatics analysis by using The Cancer Genome Atlas(TCGA)data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC.Results:Transcriptomic analysis revealed 5 NK cell subsets(L1-NK-CD56bright,L2-NK-CD56dim,L3-NK-HLA,L4-LrNK-FCGR3A,and L5-LrNK-XCL1)in the healthy liver tissues.However,the transitional L3 subset and the CXCR6+CD16+L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues.Furthermore,4 common prognosis-associated genes(RHOB,TALDO1,HLA-DPA1,and TKT)were significantly overexpressed in the paired tumor tissue and blood.Conclusions:Our study revealed 5 specific subsets of NK cells in healthy human liver tissues.However,only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues.The cytotoxic NK cell subsets were absent in HCC tissues.Furthermore,we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.

Technical advances in NK cell-based cellular immunotherapy

Natural killer(NK)cells represent a promising future for tumor immunotherapy because of their unique biological functions and characteristics.This review focuses on technical advances in NK cell-based cellular immunotherapy and summarizes the developments of recent years in cell sources,genetic modification,manufacturing systems,clinical programs,and outcomes.Future prospects and challenges in NK cell immunotherapy are also discussed,including off-the-shelf NK cell exploitation,automatic and closed manufacturing systems,cryopreservation,and therapies involving regulatory checkpoints.

Cell Therapy: A New Era of Disease Intervention

Cell therapy has been developing rapidly in recent years, and has brought forward unique perspectives, methods, and means for curing human diseases. Following surgery, chemotherapy, and radiotherapy, cell therapy is known as the “fourth weapon” in malignant tumor treatment. Significant progress has also been made in the use of cell therapy to treat tissue injuries, genetic diseases, and diabetes. In fact, cell therapy is not only a hot topic in experimental and clinical research, but also a target of industry. According to the 2017–2021 report by Technavio, an internationally renowned market research company, the global cell therapy market is expected to grow at a compound annual growth rate of 23.27% between 2017 and 2021, up to 120 billion USD by 2021. Cell therapy technology has provided new solutions for serious diseases such as malignant tumors, and has become the hope of patients fighting a losing battle with disease. In this context, Engineering, the official journal of the Chinese Academy of Engineering (CAE), has published a special issue on cell therapy. This issue is composed of eight reviews and treatises on cell therapy that cover different aspects of this field. The editorial board of this special issue is deeply grateful to all the authors, reviewers, and editors who made this special issue possible.

Bayesian inference-based wear prediction method for plain bearings under stationary mixed-friction conditions

This study introduces a method to predict the remaining useful life(RUL)of plain bearings operating under stationary,wear-critical conditions.In this method,the transient wear data of a coupled elastohydrodynamic lubrication(mixed-EHL)and wear simulation approach is used to parametrize a statistical,linear degradation model.The method incorporates Bayesian inference to update the linear degradation model throughout the runtime and thereby consider the transient,system-dependent wear progression within the RUL prediction.A case study is used to show the suitability of the proposed method.The results show that the method can be applied to three distinct types of post-wearing-in behavior:wearing-in with subsequent hydrodynamic,stationary wear,and progressive wear operation.While hydrodynamic operation leads to an infinite lifetime,the method is successfully applied to predict RUL in cases with stationary and progressive wear.

NK cell receptor imbalance and NK cell dysfunction in HBV nfection and hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus （HBV） infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer （NK） cells express a large number of immune recognition receptors （NK receptors （NKRs）） to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.

Exosomes mediate hepatitis B virus （HBV） transmission and NK-cell dysfunction

Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus （HBV） infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B （CHB） patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer （NK） cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1, r-dioctadecyl-3,3,3＇,3＇,-tetramethylindodicarbocyanine, 4-chlorobenzenesulfnate salt （DiD）-Iabeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-β treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon （IFN）-y production, cytolytic activity, NK-cell proliferation and survival, as well as the responsiveness of the cells to poly （I.C） stimulation. HBV infection suppressed the expression of pattern-recognition receptors, especially retinoic acid inducible gene I （RIG-I）, on NK cells, resulting in the dampening of the nuclear factor KB （NF-KB） and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection.

Liver natural killer cells： subsets and roles in liver immunity

The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply, With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer （NK） cells play important roles in host defense and in maintaining immune balance, Hepatic NK cells were first described as ＇pit cells＇ in the rat liver in the 1970s, Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK （cNK） cells, are present in this organ, Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit ceils and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity,

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

In December 2019,a novel coronavirus was first reported in Wuhan,China.1 It was named by the World Health Organization as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and is responsible for coronavirus disease 2019(COVID-19).Up to 28 February 2020,79,394 cases have been confirmed according to China’s National Health Commission.Outside China,the virus has spread rapidly to over 36 countries and territories.

Role of microbiota on lung homeostasis and diseases

The lungs, as a place of gas exchange, are continuously exposed to environmental stimuli, such as allergens, microbes, and pollutants. The development of the culture-independent technique for microbiological analysis, such as 16 S rRNA sequencing,has uncovered that the lungs are not sterile and, in fact, colonized by diverse communities of microbiota. The function of intestinal microbiota in modulating mucosal homeostasis and defense has been widely studied; however, the potential function of lung microbiota in regulating immunity and homeostasis has just begun. Increasing evidence indicates the relevance of microbiota to lung homeostasis and disease. In this review, we describe the distribution and composition of microbiota in the respiratory system and discuss the potential function of lung microbiota in both health and acute/chronic lung disease. In addition, we also discuss the recent understanding of the gut-lung axis, because several studies have revealed that the immunological interaction among the gut, the lung, and the microbiota was involved in this issue.

The Regulatory Effect of Natural Killer Cells:Do "NK-reg Cells" Exist?

The most important progress in immunology in the last decade is the description of regulatory lymphocytes, among which Treg cells and regulatory NKT cells are much attractive to not only immunologists but also almost all biomedical researchers. Meanwhile, it is noted that NK cells are not only ＂Killers＂ but also regulate innate and adaptive immunity, especially in early stage, by secreting cytokines and cell-cell contact. In this review, we are going to briefly summarize the progresses in regulatory lymphocytes including T cells （Treg, Tr1, Th3）, NKT cells and NK cells, and then extensively introduce the positive regulatory function of NK cells in both normal immune response and in disease condition （tumor, infection and autoimmunity）, and finally, to focus on the most latest progression in the negative regulatory effects of NK cells on normal and pathogenic immune response. In conclusion, we speculate that a ＂regulatory NK （NK-reg）＂ cell subset exist and need to explore.

Gut-liver axis:gut microbiota in shaping hepatic innate immunity

Gut microbiota play an essential role in shaping immune cell responses. The liver was continuously exposed to metabolic products of intestinal commensal bacterial through portal vein and alteration of gut commensal bateria was always associated with increased risk of liver inflammation and autoimmune disease. Considered as a unique immunological organ, the liver is enriched with a large number of innate immune cells. Herein, we summarize the available literature of gut microbiota in shaping the response of hepatic innate immune cells including NKT cells, NK cells, γδ T cells and Kupffer cells during health and disease. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of innate immune cell-related liver disease.

Hepatitis B Virus Down-Regulates Expressions of MHC Class I Molecules on Hepatoplastoma Cell Line

Chronic HBV infection is associated with a 100-fold high risk of developing hepatocellular carcinoma. Tumor recognition is of the most importance during the immune surveillance process that prevents cancer development in humans. In the present study, the expressions of MHC class Ⅰ molecules on hepatoplastoma cell line HepG2.2.15 were investigated to indicate the possible effects of HBV on the immune recognition during HBV-associated hepatocellular carcinoma. It was found that the expressions of MHC class Ⅰ molecules HLA-ABC, HLA-E and MICA were much lower in HepG2.2.15 cells compared with HepG2 cells. The expressing HBV in human hepatoplastoma cell line significantly down-regulated the expressions of MHC class Ⅰ molecules. Additionally, it was observed that in murine chronic HBsAg carriers the expression of classical MHC-I molecule on hepatocytes was down-regulated. These results demonstrated that HBV might affect the immune recognition during HBV- associated hepatocellular carcinoma such as the recognition of CD8^＋ T, NK-CTL and NK cells and prevent the immune surveillance against tumors. However, the effects of HBV down-regulation of MHC class I molecules on the target cells in vivo should be further studied. Cellular ＆ Molecular Immunology.

γδ T cells in liver diseases

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues, γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and fiver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

Natural killer cells in liver diseases

The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer （NK） cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct ＂killer＂ functions, NK cell activity contributes to regulate innate and adaptive immunity （helper or regulator）. Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.