Immunoglobulin (Ig) M production can be induced by the interaction of thymus-independent type-2 (TI-2) antigen (Ag) with B cell Ag receptors (BCRs) without the involvement of conventional T cells;for IgG production th...Immunoglobulin (Ig) M production can be induced by the interaction of thymus-independent type-2 (TI-2) antigen (Ag) with B cell Ag receptors (BCRs) without the involvement of conventional T cells;for IgG production through the same process, however, a second signal is required. Previous studies have reported that invariant natural killer T (iNKT) cells may be responsible for the second signal involved in IgG production. In the present study, we addressed whether human iNKT cells could participate in the production of Ig against TI-2 Ag in vitro. Two major distinct subsets of human iNKT cells, CD4<sup>+</sup> CD8β<sup>-</sup> (CD4) and CD4<sup>-</sup> CD8β<sup>-</sup> [double negative (DN)] cells, were generated from peripheral blood monocytes from a healthy volunteer. BCR engagement, triggered by anti-IgM antibody stimulation, examined here as a model of BCR engagement triggered by TI-2 Ag, induced abundant IgM production by B cells. Both CD4 and DN iNKT cells reduced IgM production and conversely enhanced IgG production in a dose-dependent manner. In addition, IgG production by CD19<sup>+</sup>CD27<sup>-</sup> (naïve) and CD19<sup>+</sup>CD27<sup>+</sup> (memory) B cells was predominantly promoted by DNiNKT cells rather than CD4 iNKT cells;nevertheless, IgM production by both B cell subsets was similarly reduced by either subset of iNKT cells. These results suggest that the DN iNKT subsets may preferentially promote Ig class switching by B cells upon stimulation with TI-2 Ag.展开更多
Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is ...Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α.fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers,such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article,we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.展开更多
Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options r...Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.展开更多
In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhanc...In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.展开更多
Bisphenol A(BPA)is a monomer used in manufacturing a wide range of chemical products,including epoxy resins and polycarbonate.BPA,an important endocrine disrupting chemical that exerts estrogen-like activities,is dete...Bisphenol A(BPA)is a monomer used in manufacturing a wide range of chemical products,including epoxy resins and polycarbonate.BPA,an important endocrine disrupting chemical that exerts estrogen-like activities,is detectable at nanomolar levels in human serum worldwide.The pregnancy associated doses of 17b-estradiol(E2)plus tumor-necrosis factor-a(TNF-a)induce distorted maturation of human dendritic cells(DCs)that result in an increased capacity to induce T helper(Th)2 responses.The current study demonstrated that the presence of BPA during DC maturation influences the function of human DCs,thereby polarizing the subsequent Th response.In the presence of TNF-a,BPA treatment enhanced the expression of CC chemokine ligand 1(CCL1)in DCs.In addition,DCs exposed to BPA/TNF-a produced higher levels of IL-10 relative to those of IL-12p70 on CD40 ligation,and preferentially induced Th2 deviation.BPA exerts the same effect with E2 at the same dose(0.01–0.1 mM)with regard to DC-mediated Th2 polarization.These findings imply that DCs exposed to BPA will provide one of the initial signals driving the development and perpetuation of Th2-dominated immune response in allergic reactions.展开更多
The advent of tyrosine kinase inhibitor(TKI)therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia(CML).However,the poor prognosis of patients with advanced-phase CML and the lif...The advent of tyrosine kinase inhibitor(TKI)therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia(CML).However,the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges;therefore,an effective therapeutic has been sought.The BCR–ABL p210 fusion protein’s junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy.BCR–ABL p210 fusion-region-specific CD4+T-helper(Th)cells possess antileukemic potential,but their function remains unclear.In this study,we established a BCR–ABL p210 b3a2 fusion-region-specific CD4+Th-cell clone(b3a2-specific Th clone)and examined its dendritic cell(DC)-mediated antileukemic potential.The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile.Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation,as indicated by upregulated production of CD86 and IL-12p70 by DCs,which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells.Moreover,in the presence of HLA-A*24:02-restricted Wilms tumor 1(WT1)235–243 peptide,DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes(CTLs).The expanded CTLs were cytotoxic toward WT1235–243-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo.However,the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α.Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.展开更多
文摘Immunoglobulin (Ig) M production can be induced by the interaction of thymus-independent type-2 (TI-2) antigen (Ag) with B cell Ag receptors (BCRs) without the involvement of conventional T cells;for IgG production through the same process, however, a second signal is required. Previous studies have reported that invariant natural killer T (iNKT) cells may be responsible for the second signal involved in IgG production. In the present study, we addressed whether human iNKT cells could participate in the production of Ig against TI-2 Ag in vitro. Two major distinct subsets of human iNKT cells, CD4<sup>+</sup> CD8β<sup>-</sup> (CD4) and CD4<sup>-</sup> CD8β<sup>-</sup> [double negative (DN)] cells, were generated from peripheral blood monocytes from a healthy volunteer. BCR engagement, triggered by anti-IgM antibody stimulation, examined here as a model of BCR engagement triggered by TI-2 Ag, induced abundant IgM production by B cells. Both CD4 and DN iNKT cells reduced IgM production and conversely enhanced IgG production in a dose-dependent manner. In addition, IgG production by CD19<sup>+</sup>CD27<sup>-</sup> (naïve) and CD19<sup>+</sup>CD27<sup>+</sup> (memory) B cells was predominantly promoted by DNiNKT cells rather than CD4 iNKT cells;nevertheless, IgM production by both B cell subsets was similarly reduced by either subset of iNKT cells. These results suggest that the DN iNKT subsets may preferentially promote Ig class switching by B cells upon stimulation with TI-2 Ag.
文摘Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α.fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers,such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article,we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.
文摘Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.
文摘In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.
基金This work was supported in part by the Nursing Foundation for Science Development and Innovation 09KMM06 from Chinese PLA General Hospital,Grants-in-Aid 21791572,21791473 and 20591190 from the Ministry of Education,Culture,Sports,Science and Technology(MEXT),Japan,and research grants from the Kansai Medical University(Research grant C)the Osaka Cancer Research Foundation(2010)and the Princess Takamatsu Cancer Research Fund(09-24104).
文摘Bisphenol A(BPA)is a monomer used in manufacturing a wide range of chemical products,including epoxy resins and polycarbonate.BPA,an important endocrine disrupting chemical that exerts estrogen-like activities,is detectable at nanomolar levels in human serum worldwide.The pregnancy associated doses of 17b-estradiol(E2)plus tumor-necrosis factor-a(TNF-a)induce distorted maturation of human dendritic cells(DCs)that result in an increased capacity to induce T helper(Th)2 responses.The current study demonstrated that the presence of BPA during DC maturation influences the function of human DCs,thereby polarizing the subsequent Th response.In the presence of TNF-a,BPA treatment enhanced the expression of CC chemokine ligand 1(CCL1)in DCs.In addition,DCs exposed to BPA/TNF-a produced higher levels of IL-10 relative to those of IL-12p70 on CD40 ligation,and preferentially induced Th2 deviation.BPA exerts the same effect with E2 at the same dose(0.01–0.1 mM)with regard to DC-mediated Th2 polarization.These findings imply that DCs exposed to BPA will provide one of the initial signals driving the development and perpetuation of Th2-dominated immune response in allergic reactions.
文摘The advent of tyrosine kinase inhibitor(TKI)therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia(CML).However,the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges;therefore,an effective therapeutic has been sought.The BCR–ABL p210 fusion protein’s junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy.BCR–ABL p210 fusion-region-specific CD4+T-helper(Th)cells possess antileukemic potential,but their function remains unclear.In this study,we established a BCR–ABL p210 b3a2 fusion-region-specific CD4+Th-cell clone(b3a2-specific Th clone)and examined its dendritic cell(DC)-mediated antileukemic potential.The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile.Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation,as indicated by upregulated production of CD86 and IL-12p70 by DCs,which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells.Moreover,in the presence of HLA-A*24:02-restricted Wilms tumor 1(WT1)235–243 peptide,DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes(CTLs).The expanded CTLs were cytotoxic toward WT1235–243-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo.However,the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α.Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.
