Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy...Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.展开更多
The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the...The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.展开更多
Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, incl...Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4+ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.展开更多
Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individual...Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy(ART)is limited.Methods:We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders(INRs)with poor CD4+T-cell recovery(<500 cells/μL after 4 years of ART)and 34 immunological responders(IRs)with improved CD4+T-cell recovery(>500 cells/μL after 4 years of ART).NK cell phenotype,receptor repertoire,and early activation in INRs and IRs were investigated by flow cytometry.Results:A significantly higher proportion of CD56dimCD16dim/-NK cells was observed in INRs than IRs before ART and after 4 years of ART.The number of CD56dimCD16dim/-NK cells was inversely correlated with CD4+T-cell counts in INRs before ART(r=-0.344,P=0.050).The more CD69-expressing NK cells there were,the lower the CD4+T-cell counts andΔCD4,and these correlations were observed in INRs after ART(r=-0.416,P=0.019;r=-0.509,P=0.003,respectively).Additionally,CD69-expressing CD56dimCD16dim/-NK cells were more abundant in INRs than those in IRs(P=0.018)after ART,both of which had an inverse association trend towards significance with CD4+T-cell counts.The expression of the activating receptors NKG2C,NKG2D,and NKp46 on CD56dimCD16dim/-NK cell subsets were higher in IRs than that in INRs after 4 years of ART(all P<0.01).Strong inverse correlations were observed between CD69 expression and NKG2C,NKG2A-NKG2C+,NKG2D,and NKp46 expression on CD56dimCD16dim/-NK cells in INRs after ART(NKG2C:r=-0.491,P=0.004;NKG2A-NKG2C+:r=-0.434,P=0.013;NKG2D:r=-0.405,P=0.021;NKp46:r=-0.457,P=0.008,respectively).Conclusions:INRs had a larger number of CD56dimCD16dim/-NK cells characterized by higher activation levels than did IRs after ART.The increase in the CD56dimCD16dim/-NK cell subset may play an adverse role in immune reconstitution.Further functional studies of CD56dimCD16dim/-NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.展开更多
Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected pat...Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected patients is unknown.This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders(INRs)receiving antiretroviral therapy(ART).Methods:From February to April 2018,a prospective,randomized,controlled,open-label clinical trial,which enrolled 20 HIV-1 INRs following specific inclusion criteria,was conducted at Nankai University Second People’s Hospital.Participants were randomly allocated(simple randomization 1:1)to either the combined treatment(NK+ART)group(n=10)or the control(ART)group(n=10).The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor(KIR)/human leukocyte antigen(HLA)-Cw mismatched healthy donor were prepared(108 cells in each injection)and intravenously infused to each recruited patient of NK+ART group in three courses.Key immune parameters(CD4 count,CD8 count,CD4/CD8 ratio),laboratory tests(count of blood cells,biochemistry panel)and symptoms at baseline and at month 1,3,6,9,12,and 24 were measured/collected to analyze the safety and efficacy of the therapy.Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance(ANOVA)test.Generalized estimating equations(GEE)model was performed to evaluate the overall effect of the NK+ART group vs.the ART group.Results:From baseline to 24 months,we noted a mean CD4 count augmentation(139 to 243 cells/μL)in the NK+ART group and(144 to 176 cells/μL)in the ART group(difference,67;95%CI,10 to 124;P=0.024).Our estimations revealed that NK+ART group could improve CD4 level(β=54.59,P=0.006)and CD8 level(β=322.47,P=0.010)on average among the six measurements compared with the ART group.Only two(2/10,20%)participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs,allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio.The practical effects,however,need long-term follow-up observations.Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912(No.ChiCTR1900020634).展开更多
Lipid droplet(LD)in vegetative tissues has recently been implicated in environmental responses in plants,but its regulation and its function in stress tolerance are not well understood.Here,we identified a Membrane Oc...Lipid droplet(LD)in vegetative tissues has recently been implicated in environmental responses in plants,but its regulation and its function in stress tolerance are not well understood.Here,we identified a Membrane Occupation and Recognition Nexus 1(MORN1)gene as a contributor to natural variations of stress tolerance through genome-wide association study in Arabidopsis thaliana.Characterization of its loss-of-function mutant and natural variants revealed that the MORN1 gene is a positive regulator of plant growth,disease resistance,cold tolerance,and heat tolerance.The MORN1 protein is associated with the Golgi and is also partly associated with LD.Protein truncations that disrupt these associations abolished the biological function of the MORN1 protein.Furthermore,the MORN1 gene is a positive regulator of LD abundance,and its role in LD number regulation and stress tolerance is highly linked.Therefore,this study identifies MORN1 as a positive regulator of LD abundance and a contributor to natural variations of stress tolerance.It implicates a potential involvement of Golgi in LD biogenesis and strongly suggests a contribution of LD to diverse processes of plant growth and stress responses.展开更多
文摘Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.
文摘The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.
文摘Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4+ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.
基金National Natural Science Foundation of China(Nos.81772165,81974303,81571973,and 82072271)the NSFC-NIH Biomedical collaborative research program(No.81761128001)+3 种基金the National 13th Five-Year Grand Program on Key Infectious Disease Control(Nos.2017ZX10202102-005-003 and 2017ZX10202101-004-001)the Beijing Municipal of Science and Technology Major Project(No.D161100000416003)the Beijing Key Laboratory for HIV/AIDS Research(No.BZ0089)the Key Project of Tianjin Second People’s Hospital(No.YS0001)。
文摘Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy(ART)is limited.Methods:We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders(INRs)with poor CD4+T-cell recovery(<500 cells/μL after 4 years of ART)and 34 immunological responders(IRs)with improved CD4+T-cell recovery(>500 cells/μL after 4 years of ART).NK cell phenotype,receptor repertoire,and early activation in INRs and IRs were investigated by flow cytometry.Results:A significantly higher proportion of CD56dimCD16dim/-NK cells was observed in INRs than IRs before ART and after 4 years of ART.The number of CD56dimCD16dim/-NK cells was inversely correlated with CD4+T-cell counts in INRs before ART(r=-0.344,P=0.050).The more CD69-expressing NK cells there were,the lower the CD4+T-cell counts andΔCD4,and these correlations were observed in INRs after ART(r=-0.416,P=0.019;r=-0.509,P=0.003,respectively).Additionally,CD69-expressing CD56dimCD16dim/-NK cells were more abundant in INRs than those in IRs(P=0.018)after ART,both of which had an inverse association trend towards significance with CD4+T-cell counts.The expression of the activating receptors NKG2C,NKG2D,and NKp46 on CD56dimCD16dim/-NK cell subsets were higher in IRs than that in INRs after 4 years of ART(all P<0.01).Strong inverse correlations were observed between CD69 expression and NKG2C,NKG2A-NKG2C+,NKG2D,and NKp46 expression on CD56dimCD16dim/-NK cells in INRs after ART(NKG2C:r=-0.491,P=0.004;NKG2A-NKG2C+:r=-0.434,P=0.013;NKG2D:r=-0.405,P=0.021;NKp46:r=-0.457,P=0.008,respectively).Conclusions:INRs had a larger number of CD56dimCD16dim/-NK cells characterized by higher activation levels than did IRs after ART.The increase in the CD56dimCD16dim/-NK cell subset may play an adverse role in immune reconstitution.Further functional studies of CD56dimCD16dim/-NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.
基金This study was funded by the Key Project of Tianjin Second People’s Hospital(No.YS0001)the National Natural Science Foundation of China(No.82002136)the 13th Five-year National Major Project for HIV/AIDS and Hepatitis B Control and Prevention,and the Chinese Ministry of Science and Technology(Nos.2017ZX10202102005004,2018ZX10302104-002)。
文摘Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected patients is unknown.This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders(INRs)receiving antiretroviral therapy(ART).Methods:From February to April 2018,a prospective,randomized,controlled,open-label clinical trial,which enrolled 20 HIV-1 INRs following specific inclusion criteria,was conducted at Nankai University Second People’s Hospital.Participants were randomly allocated(simple randomization 1:1)to either the combined treatment(NK+ART)group(n=10)or the control(ART)group(n=10).The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor(KIR)/human leukocyte antigen(HLA)-Cw mismatched healthy donor were prepared(108 cells in each injection)and intravenously infused to each recruited patient of NK+ART group in three courses.Key immune parameters(CD4 count,CD8 count,CD4/CD8 ratio),laboratory tests(count of blood cells,biochemistry panel)and symptoms at baseline and at month 1,3,6,9,12,and 24 were measured/collected to analyze the safety and efficacy of the therapy.Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance(ANOVA)test.Generalized estimating equations(GEE)model was performed to evaluate the overall effect of the NK+ART group vs.the ART group.Results:From baseline to 24 months,we noted a mean CD4 count augmentation(139 to 243 cells/μL)in the NK+ART group and(144 to 176 cells/μL)in the ART group(difference,67;95%CI,10 to 124;P=0.024).Our estimations revealed that NK+ART group could improve CD4 level(β=54.59,P=0.006)and CD8 level(β=322.47,P=0.010)on average among the six measurements compared with the ART group.Only two(2/10,20%)participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs,allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio.The practical effects,however,need long-term follow-up observations.Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912(No.ChiCTR1900020634).
基金supported by National Science Foundation USA(IOS-1946174)to J.H.Cornell-ZJU seed grant+1 种基金Seed Grant of Cornell Institute of Biotechnologythe Major Science and Technology Research Projects of Guangdong Laboratory for Lingnan Modern Agriculture(NT2021001)。
文摘Lipid droplet(LD)in vegetative tissues has recently been implicated in environmental responses in plants,but its regulation and its function in stress tolerance are not well understood.Here,we identified a Membrane Occupation and Recognition Nexus 1(MORN1)gene as a contributor to natural variations of stress tolerance through genome-wide association study in Arabidopsis thaliana.Characterization of its loss-of-function mutant and natural variants revealed that the MORN1 gene is a positive regulator of plant growth,disease resistance,cold tolerance,and heat tolerance.The MORN1 protein is associated with the Golgi and is also partly associated with LD.Protein truncations that disrupt these associations abolished the biological function of the MORN1 protein.Furthermore,the MORN1 gene is a positive regulator of LD abundance,and its role in LD number regulation and stress tolerance is highly linked.Therefore,this study identifies MORN1 as a positive regulator of LD abundance and a contributor to natural variations of stress tolerance.It implicates a potential involvement of Golgi in LD biogenesis and strongly suggests a contribution of LD to diverse processes of plant growth and stress responses.