Tumor immunotherapy: New aspects of natural killer cells

A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies,gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer（NK） cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients. Therapeutic antibodies, chimeric antigen receptor（CAR）, or bispecific proteins can all retarget NK cells precisely to tumor cells. Therapeutic antibody blockade of the immune checkpoints of NK cells has been suggested to overcome the immunosuppressive signals delivered to NK cells.Oncolytic virotherapy provokes antitumor activity of NK cells by triggering antiviral immune responses. Herein,we review the current immunotherapeutic approaches employed to restore NK cell antitumor functionality for the treatment of cancer.

Natural killer cells in tumor immunotherapy

Cancer is the second most common cause of death worldwide and remains one of the critical public health problems of our time1.Recently,immunotherapy has considerably improved the outcomes of patients with advanced cancers.Immune checkpoint blockade and chimeric antigen receptor(CAR)-T cell-based therapies have achieved remarkable success in recent decades,thus placing the host immune response in the spotlight as a potential new approach in antitumor therapy.

Regional immunity in tissue homeostasis and diseases

The immune system functions in the organ/tissue of the body.The immune cell differentiation and function are influenced by the organ/tissue microenvironments in which they reside,and the interaction of immune cells with the organ/tissue microenvironments may affect and even determine the outcome of the immune responses(Hu and Pasare,2013;Zajac and Harrington,2014).It has been

Transcriptomic characteristics and impaired immune function of patients who retest positive for SARS-CoV-2 RNA

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,has become a global public health crisis.Some patients who have recovered from COVID-19 subsequently test positive again for SARS-CoV-2 RNA after discharge from hospital.How such retest-positive(RTP)patients become infected again is not known.In this study,30 RTP patients,20 convalescent patients,and 20 healthy controls were enrolled for the analysis of immunological characteristics of their peripheral blood mononuclear cells.We found that absolute numbers of CD4^(+)T cells,CD8^(+)T cells,and natural killer cells were not substantially decreased in RTP patients,but the expression of activation markers on these cells was significantly reduced.The percentage of granzyme B-producing T cells was also lower in RTP patients than in convalescent patients.Through transcriptome sequencing,we demonstrated that high expression of inhibitor of differentiation 1(ID1)and low expression of interferon-induced transmembrane protein 10(IFITM10)were associated with insufficient activation of immune cells and the occurrence of RTP.These findings provide insight into the impaired immune function associated with COVID-19 and the pathogenesis of RTP,which may contribute to a better understanding of the mechanisms underlying RTP.

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,

Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface

During early pregnancy,an orchestrated evolutionary maternal adaption toward tolerance of the semiallogeneic fetus is required to ensure decidualization and early embryo development.Remodeling of the immune system involves natural killer cells(NKs),macrophages,T cells and dendritic cells(DCs) altering the microenvironment in the deciduas.In particular,a unique population of NK cells with a CD56^(bright)CD16^- phenotype in the decidua has been proposed to play a key role in the maternal adaptation to pregnancy.However,there is a tendency for pregnancy immunology to reflect transplantation immunology regarding the assumption that the maternal immune system should be suppressed.This tendency is misleading.We discuss how the immune system is formed in early deciduas and the interactions between maternal NK cells and fetal growth.We propose that the maternal immune response must not be fully suppressed and is even necessary for the local response of uterine NK cells.

Challenges of NK cell-based immunotherapy in the new era

Natural killer cells （NKs） have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells （PBMCs）, stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

Liver-resident NK cells and their potential functions

Natural killer(NK)cells represent a heterogeneous population of innate lymphocytes with phenotypically and functionally distinct subsets.In particular,recent studies have identified a unique subset of NK cells residing within the liver that are maintained as tissue-resident cells,confer antigen-specific memory responses and exhibit different phenotypical and developmental characteristics compared with conventional NK(cNK)cells.These findings have encouraged researchers to uncover tissue-resident NK cells at other sites,and detailed analyses have revealed that these tissue-resident NK cells share many similarities with liver-resident NK cells and tissue-resident memory T cells.Here,we present a brief historical perspective on the discovery of liver-resident NK cells and discuss their relationship to cNK cells and other emerging NK cell subsets and their potential functions.

Cytokine storm and translating IL-6 biology into effective treatments for CoVID-19

As of May 3,2023,the Coronavirus disease 2019(COVID-19)pandemic has resulted in more than 760 million confirmed cases and over 6.9 million deaths.Several patients have developed pneumonia,which can deteriorate into acute respiratory distress syndrome.The primary etiology may be attributed to cytokine storm,which is triggered by the excessive release of proinflammatory cytokines and subsequently leads to immune dysregulation.Considering that high levels of interleukin-6(IL-6)have been detected in several highly pathogenic coronavirus-infected diseases,such as severe acute respiratory syndrome in 2002,the Middle East respiratory syndrome in 2012,and COVID-19,the IL-6 pathway has emerged as a key in the pathogenesis of this hyperinflammatory state.Thus,we review the history of cytokine storm and the process of targeting IL-6 signaling to elucidate the pivotal role played by tocilizumab in combating COVID-19.

Restoration of HBV-specific CD8+T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-αtherapy

Patients with chronic hepatitis B(CHB)undergoing interferon(IFN)-α-based therapies often exhibit a poor HBeAg serological response.Thus,there is an unmet need for new therapies aimed at CHB.This study comprised two clinical trials,including 130 CHB patients,who were treatment-naïve;in the first,92 patients were systematically analyzed ex vivo for interleukin-2 receptor(IL-2R)expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy.In our second clinical trial,38 non-responder patients,in whom IFN-αtherapy had failed,were treated with or without low-dose IL-2 for 24 weeks.We then examined the hepatitis B virus(HBV)-specific CD8+T-cell response and the clinical outcome,in these patients.Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders,we observed a decrease in CD25 expression on their CD4+T cells,suggesting that IFN-αtherapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells(Tregs).Following sequential therapy with IL-2,we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1(PD-1)expression.In addition,sequential IL-2 administration rescued effective immune function,involving signal transducer and activator of transcription 1(STAT1)activation.Importantly,IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+T cells,which translated into improved clinical outcomes,including HBeAg seroconversion,among the non-responder CHB patients.Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.

Tissue-resident natural killer cells in the livers

Nature killer(NK) cells are important lymphocytes of the innate immune system,well known for their pivotal roles in immune surveillance and defense against tumor and virus-infected cells.Current studies have revealed that NK cells are not a homogeneous population,but instead consist of distinct subsets with diverse characteristics.As an organ with predominant innate immunity,the liver is enriched with NK cells,among which two distinct NK cell subsets have recently been identified:conventional NK(cNK)cells and tissue-resident NK(trNK) cells.Liver trNK cells are markedly different from cNK cells in many aspects,representing a new lineage of innate lymphoid cell(ILC) family.Here,we summarize the phenotypic and functional features of liver trNK cells,and review current knowledge regarding developmental pathway of liver trNK cells.We also overview recent advances in human liver trNK cells and discuss the striking shared hallmarks of trNK cells in different tissues.

Pyroptotic macrophages stimulate the SARS-CoV-2-associated cytokine storm

Coronavirus disease 2019(COVID-19)is an unprecedented pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).As of 22 February 2021,the worldwide pandemic has resulted in more than 110 million cases and 2.4 million deaths.1 Clinical investigation of COVID-19 patients has shown that a systemic cytokine storm can occur,especially in severe cases.2 Treatment of the SARS-CoV-2-associated cytokine storm with tocilizumab3 or anakinra4 has been shown to immediately improve the clinical outcome in most severe and critical COVID-19 patients.These data highlight the systemic cytokine storm as an important exacerbating event in severe COVID-19;however,our understanding of the molecular mechanisms involved in the initiation of the SARS-CoV-2-associated cytokine storm is limited.In the present study,we uncovered a reasonable explanation for cytokine storm initiation through the analysis of 13 autopsy samples from severe COVID-19 patients.