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 hep...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.展开更多
Objective To evaluate the effects of ethyl-acetate fraction （EAF） of extracts from Tetrastigma hemsleyanum Diels et. Gilg （TDG） on immune functions of ICR mice. Methods ICR mice were exposed to different doses of ...Objective To evaluate the effects of ethyl-acetate fraction （EAF） of extracts from Tetrastigma hemsleyanum Diels et. Gilg （TDG） on immune functions of ICR mice. Methods ICR mice were exposed to different doses of EAF for 15 or 30 days and then their immune functions were analyzed, including ConA-induced splenic lymphocyte transformation, SRBC- induced delayed type hypersensitivity response, serum hemolysin analysis, antibody-producing cells, peritoneal macrophage phagocytized chicken red blood cells, natural killer cell activity, and serum level of cytoldnes. Results EAF of extracts from TDG at different doses had various effects on immune functions of ICR mice. As compared with the controls, it increased the mouse spleen lymphocyte transformation induced by ConA, the left-hind voix pedis thickness and the number of plague forming cells （PFCs） at the dose of 1.82 mg/mL, 5.48 mg/mL, and 9.12 mg/mL, respectively; increased the ink clearance ability at the dose of 0.91 mg/mL, 1.82 mg/mL, 5.48 mg/mL, and 9.12 mg/mL, respectively; increased the phagocytosis index of mononuclear-macrophages and production of serum interferon-gamma （IFN-？） at the dose of 5.48 mg/mL; and could promote the production of serum tumor necrosis factor-alpha （TNF-α） at the dose of 9.12 mg/mL. Conclusion EAF of extracts from TDG can regulate mouse immune functions in vivo.展开更多
Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immu...Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.展开更多
NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surfa...NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors.In humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and NKG2D.Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor transformation.The HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells.Other receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell tolerance.PD-1 also may be expressed by NK cells in cancer patients.Since PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK cells.Thus,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions.Recently,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation.Since most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging results.The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.展开更多
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 ...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,展开更多
For predominant abundance with liver-specific Kupffer cells, natural killer （NK） cells, and natural killer T （NKT） cdls and their rapid responses to several stimuli, the liver is considered as an organ with innate...For predominant abundance with liver-specific Kupffer cells, natural killer （NK） cells, and natural killer T （NKT） cdls and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features. In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A （Con A）, lipopolysaccharide （LPS）, or polyinosinic-polycytidylic acid （Poly I：C）-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.展开更多
The incidence of gastric cancer(GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancerrelated deaths with a case fatality GC ratio higher than ...The incidence of gastric cancer(GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancerrelated deaths with a case fatality GC ratio higher than other common malignancies. Surgical resection is the primary curative treatment for GC though the overall 5-year survival rate remains poor(approximately 20%-25%). To improve the outcome of resectable gastric cancer, different treatment strategies have been evaluated such as adjuvant or perioperative chemotherapy. In resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit. Moreover, in metastatic patients, chemotherapy is the mainstay of palliative therapy with a median overall survival of 8-10 mo and objective response rates of merely 20%-40%. Therefore, the potential for making key beneficial progress is to investigate the GC molecular biology to realize innovative therapeutic strategies, such as specific immunotherapy. In this review, we provide a panoramic view of the different immune-based strategies used for gastric cancer treatment and the results obtained in the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell-based immunotherapies.展开更多
Background The response of patients with chronic hepatitis B （CHB） to antiviral therapy against hepatitis B virus （HBV） is related to the base line level of HBV DNA, but the mechanism is not clear. The present stu...Background The response of patients with chronic hepatitis B （CHB） to antiviral therapy against hepatitis B virus （HBV） is related to the base line level of HBV DNA, but the mechanism is not clear. The present study aimed to understand the possible relationship between the level of HBV DNA and HBV-specific, nonspecific cytotoxic T lymphocytes （CTL） and natural killer （NK） cells of CHB patients and the mechanism how the HBV DNA level influences the antiviral therapeutic effect. Methods Totally 100 adult patients with CHB who were positive for HBV DNA, HBeAg and （HLA）-A2 were enrolled into this study. HBV DNA was tested by real time fluorescence quantitative polymerase chain reaction （PCR）. HBV specific and nonspecific CTL and NK cells were tested by flowcytometry. Serum alanine aminotransferase （ALT） and total bilirubin （TBil） were determined for each patient using routine biochemical tests. The 100 cases were assigned to two groups based on their HBV DNA level： group A had 48 cases, their HBV DNA level was 104-105 copies/ml, group B had 52 cases their HBV DNA level was 106-107 copies/ml. HBV specific CTL, nonspecific CTL, NK cells, ALT and TBil of the two groups were compared. Results HBV DNA level of groups A and B was （4.81±0.39） log10 copies/ml and （6.81±0.40） log10 copies/ml, respectively （t=25.32, P 〈0.001）. HBV specific CTL and NK cells of group A were significantly higher than those of group B （P 〈0.001 for both）. Nonspecific CTL of group A was significantly lower than that of group B （P 〈0.01）. ALT and TBil of group A were significantly lower than those of group B （P 〈0.01 and P 〈0.05, respectively）. Conclusions Serum HBV DNA level of patients with CHB is related to HBV specific CTL, nonspecific CTL and NK cells, which might result in inflammatory reaction of liver and cause more damage to liver function. Mechanism of HBV DNA level affecting the efficacy of anti-viral treatment may be related to the levels of HBV specific CTL and NK cel展开更多
Objective: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer(NK) cells.Methods: We em...Objective: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer(NK) cells.Methods: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D(NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species(ROS) and mitochondrial ROS using DCFH-DA and MitoSOX^(TM) probe,respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex Ⅰ/Ⅲ kits.Results: Our investigation revealed that TWS119 downregulated NKG2D ligands(H60 a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of p Ser9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex Ⅰ/Ⅲ function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands(Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS.Conclusions: The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells,which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy.展开更多
Interleukin-18 （IL-18） was discovered as an interferon-y-inducing factor and had a critical role in inflammatory and immune respouse. It stimulates natural killer （NK） and T cells and enhances Thl immune response....Interleukin-18 （IL-18） was discovered as an interferon-y-inducing factor and had a critical role in inflammatory and immune respouse. It stimulates natural killer （NK） and T cells and enhances Thl immune response. These activated immune cells eliminate cancer cells and virus-infected cells effectively. However, IL-18 has also been found to promote tumor progression. Higher expression or secretion level of IL-18 is detected in various cancer cells in comparison with normal control, and IL-18 is able to induce angiogenesis, migration/metastasis, proliferation and immune escape. These dual effects and the mechanism of IL-18 need to be investigated further as it relates to cancer.展开更多
AIM： To assess if a specific cytotoxic T cell response can be induced in patients with malignant liver tumors treated with radio-frequency ablation （RFA）. METHODS： Six Patients with liver metastases of colorectal ...AIM： To assess if a specific cytotoxic T cell response can be induced in patients with malignant liver tumors treated with radio-frequency ablation （RFA）. METHODS： Six Patients with liver metastases of colorectal cancer and 6 with hepatocellular carcinoma （HCC） underwent RFA. Blood was sampled before, 4 and 8 wk after RFA. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. Peripheral T cell activation was assessed by an interferon gamma （IFNγ） secretion assay and flow cytometry. T cells were double-stained for CD4/CD8 and IFNγ to detect cytotoxic T cells. The ratio of IFNγ positive and IFNγ negative T cells was determined as the stimulation index （SI）. To assess cytolytic activity, T cells were co-incubated with human CaCo colorectal cancer and HepG2 HCC cells and release of cytosolic adenylate kinase was measured by a luciferase assay. RESULTS： Before RFA SI was 0.021 （±0.006） for CD4^＋ and 0.022 （± 0.004） for CD8^＋T cells against nonmalignant liver tissue and 0.018 （± 0.005） for CD4^＋ and 0.021 （± 0.004） for CD8^＋ cells against autologous tumor tissue. Four weeks after RFA SI against tumor tissue increased to 0.109 （± 0.005） for CD4＋ and 0.11 （± 0.012） for CD8＋ T cells against HCC, and to 0.115 （± 0.031） for CD4^＋ and 0.15 （± 0.02） for CD8^＋ cells for colorectal metastases （P 〈 0.0001）. No increased SI was observed with nonmalignant tumor tissue at all time points. Before RFA cytolytic activity against the respect（ve cancer cells was low with 2.62 （± 0.37） relative luminescence units （RLU）, but rose more than 100 fold 4 and 8 wk after RFA. Spontaneous release was 〈 2% of maximum release in all experiments. CONCLUSION： Patients with primary and secondary tumors of the liver show a significant tumor-specific cytotoxic T-cell stimulation with a dramatically increased tumor specific cytolytic activity of CD8^＋ T cells after RFA.展开更多
基金This work was supported by grants from the National Basic Research Program of China （No. 2013CB531503）, the Natural Science Foundation of China （Nos. 81172789 and 30972692）.
文摘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.
基金the Scientific Research Foundation of Health Bureau of Zhejiang Province (No. 2006c151)
文摘Objective To evaluate the effects of ethyl-acetate fraction （EAF） of extracts from Tetrastigma hemsleyanum Diels et. Gilg （TDG） on immune functions of ICR mice. Methods ICR mice were exposed to different doses of EAF for 15 or 30 days and then their immune functions were analyzed, including ConA-induced splenic lymphocyte transformation, SRBC- induced delayed type hypersensitivity response, serum hemolysin analysis, antibody-producing cells, peritoneal macrophage phagocytized chicken red blood cells, natural killer cell activity, and serum level of cytoldnes. Results EAF of extracts from TDG at different doses had various effects on immune functions of ICR mice. As compared with the controls, it increased the mouse spleen lymphocyte transformation induced by ConA, the left-hind voix pedis thickness and the number of plague forming cells （PFCs） at the dose of 1.82 mg/mL, 5.48 mg/mL, and 9.12 mg/mL, respectively; increased the ink clearance ability at the dose of 0.91 mg/mL, 1.82 mg/mL, 5.48 mg/mL, and 9.12 mg/mL, respectively; increased the phagocytosis index of mononuclear-macrophages and production of serum interferon-gamma （IFN-？） at the dose of 5.48 mg/mL; and could promote the production of serum tumor necrosis factor-alpha （TNF-α） at the dose of 9.12 mg/mL. Conclusion EAF of extracts from TDG can regulate mouse immune functions in vivo.
文摘Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.
文摘NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis.The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors.In humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and NKG2D.Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor transformation.The HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells.Other receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell tolerance.PD-1 also may be expressed by NK cells in cancer patients.Since PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK cells.Thus,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions.Recently,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation.Since most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging results.The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.
基金This work was supported by the Ministry of Science ＆ Technology of China （973 Basic Science Project #2013CB944902）, the Natural Science Foundation of China （#81361120388, #31300727, and #81571522）, and the Key Program of the Chinese Academy of Sciences （KJZD-EW-L10 -003）.
文摘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,
文摘For predominant abundance with liver-specific Kupffer cells, natural killer （NK） cells, and natural killer T （NKT） cdls and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features. In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A （Con A）, lipopolysaccharide （LPS）, or polyinosinic-polycytidylic acid （Poly I：C）-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.
基金Supported by grant from the Italian Ministry of University and Research,No.Prin 2009FZZ4XM_002
文摘The incidence of gastric cancer(GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancerrelated deaths with a case fatality GC ratio higher than other common malignancies. Surgical resection is the primary curative treatment for GC though the overall 5-year survival rate remains poor(approximately 20%-25%). To improve the outcome of resectable gastric cancer, different treatment strategies have been evaluated such as adjuvant or perioperative chemotherapy. In resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit. Moreover, in metastatic patients, chemotherapy is the mainstay of palliative therapy with a median overall survival of 8-10 mo and objective response rates of merely 20%-40%. Therefore, the potential for making key beneficial progress is to investigate the GC molecular biology to realize innovative therapeutic strategies, such as specific immunotherapy. In this review, we provide a panoramic view of the different immune-based strategies used for gastric cancer treatment and the results obtained in the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell-based immunotherapies.
文摘Background The response of patients with chronic hepatitis B （CHB） to antiviral therapy against hepatitis B virus （HBV） is related to the base line level of HBV DNA, but the mechanism is not clear. The present study aimed to understand the possible relationship between the level of HBV DNA and HBV-specific, nonspecific cytotoxic T lymphocytes （CTL） and natural killer （NK） cells of CHB patients and the mechanism how the HBV DNA level influences the antiviral therapeutic effect. Methods Totally 100 adult patients with CHB who were positive for HBV DNA, HBeAg and （HLA）-A2 were enrolled into this study. HBV DNA was tested by real time fluorescence quantitative polymerase chain reaction （PCR）. HBV specific and nonspecific CTL and NK cells were tested by flowcytometry. Serum alanine aminotransferase （ALT） and total bilirubin （TBil） were determined for each patient using routine biochemical tests. The 100 cases were assigned to two groups based on their HBV DNA level： group A had 48 cases, their HBV DNA level was 104-105 copies/ml, group B had 52 cases their HBV DNA level was 106-107 copies/ml. HBV specific CTL, nonspecific CTL, NK cells, ALT and TBil of the two groups were compared. Results HBV DNA level of groups A and B was （4.81±0.39） log10 copies/ml and （6.81±0.40） log10 copies/ml, respectively （t=25.32, P 〈0.001）. HBV specific CTL and NK cells of group A were significantly higher than those of group B （P 〈0.001 for both）. Nonspecific CTL of group A was significantly lower than that of group B （P 〈0.01）. ALT and TBil of group A were significantly lower than those of group B （P 〈0.01 and P 〈0.05, respectively）. Conclusions Serum HBV DNA level of patients with CHB is related to HBV specific CTL, nonspecific CTL and NK cells, which might result in inflammatory reaction of liver and cause more damage to liver function. Mechanism of HBV DNA level affecting the efficacy of anti-viral treatment may be related to the levels of HBV specific CTL and NK cel
基金supported by grants from the National Natural Science Foundation of China (Grant No. 8117975 and 31770968)Tianjin Institutes for Basic Sciences (Grant No. 15JCYBJC26900 and 16JCQNJC11700)
文摘Objective: To examine the effect of pSer9-GSK-3β on breast cancer and to determine whether the underlying metabolic and immunological mechanism is associated with ROS/eIF2B and natural killer(NK) cells.Methods: We employed TWS119 to inactivate GSK-3β by phosphorylating Ser9 and explored its effect on breast cancer and NK cells. The expression of GSK-3β, natural killer group 2 member D(NKG2D) ligands, eIF2B was quantified by PCR and Western blot. We measured intracellular reactive oxygen species(ROS) and mitochondrial ROS using DCFH-DA and MitoSOX^(TM) probe,respectively, and conducted quantitative analysis of cellular respiration on 4T1 cells with mitochondrial respiratory chain complex Ⅰ/Ⅲ kits.Results: Our investigation revealed that TWS119 downregulated NKG2D ligands(H60 a and Rae1), suppressed the cytotoxicity of NK cells, and promoted the migration of 4T1 murine breast cancer cells. Nevertheless, LY290042, which attenuates p-GSK-3β formation by inhibiting the PI3K/Akt pathway, reversed these effects. We also found that higher expression of p Ser9-GSK-3β induced higher levels of ROS, and observed that abnormality of mitochondrial respiratory chain complex Ⅰ/Ⅲ function induced the dysfunction of GSK-3β-induced electron transport chain, naturally disturbing the ROS level. In addition, the expression of NOX3 and NOX4 was significantly up-regulated, which affected the generation of ROS and associated with the metastasis of breast cancer. Furthermore, we found that the expression of pSer535-eIF2B promoted the expression of NKG2D ligands(Mult-1 and Rae1) following by expression of pSer9-GSK-3β and generation of ROS.Conclusions: The PI3K/Akt/GSK-3β/ROS/eIF2B pathway could regulate NK cell activity and sensitivity of tumor cells to NK cells,which resulted in breast cancer growth and lung metastasis. Thus, GSK-3β is a promising target of anti-tumor therapy.
文摘Interleukin-18 （IL-18） was discovered as an interferon-y-inducing factor and had a critical role in inflammatory and immune respouse. It stimulates natural killer （NK） and T cells and enhances Thl immune response. These activated immune cells eliminate cancer cells and virus-infected cells effectively. However, IL-18 has also been found to promote tumor progression. Higher expression or secretion level of IL-18 is detected in various cancer cells in comparison with normal control, and IL-18 is able to induce angiogenesis, migration/metastasis, proliferation and immune escape. These dual effects and the mechanism of IL-18 need to be investigated further as it relates to cancer.
基金Supported by the Bavarian Ministry of Economy (Leitprojekt Medizintechnik) and the Hans L(o|¨)wel Foundation, Bamberg,Germany
文摘AIM： To assess if a specific cytotoxic T cell response can be induced in patients with malignant liver tumors treated with radio-frequency ablation （RFA）. METHODS： Six Patients with liver metastases of colorectal cancer and 6 with hepatocellular carcinoma （HCC） underwent RFA. Blood was sampled before, 4 and 8 wk after RFA. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. Peripheral T cell activation was assessed by an interferon gamma （IFNγ） secretion assay and flow cytometry. T cells were double-stained for CD4/CD8 and IFNγ to detect cytotoxic T cells. The ratio of IFNγ positive and IFNγ negative T cells was determined as the stimulation index （SI）. To assess cytolytic activity, T cells were co-incubated with human CaCo colorectal cancer and HepG2 HCC cells and release of cytosolic adenylate kinase was measured by a luciferase assay. RESULTS： Before RFA SI was 0.021 （±0.006） for CD4^＋ and 0.022 （± 0.004） for CD8^＋T cells against nonmalignant liver tissue and 0.018 （± 0.005） for CD4^＋ and 0.021 （± 0.004） for CD8^＋ cells against autologous tumor tissue. Four weeks after RFA SI against tumor tissue increased to 0.109 （± 0.005） for CD4＋ and 0.11 （± 0.012） for CD8＋ T cells against HCC, and to 0.115 （± 0.031） for CD4^＋ and 0.15 （± 0.02） for CD8^＋ cells for colorectal metastases （P 〈 0.0001）. No increased SI was observed with nonmalignant tumor tissue at all time points. Before RFA cytolytic activity against the respect（ve cancer cells was low with 2.62 （± 0.37） relative luminescence units （RLU）, but rose more than 100 fold 4 and 8 wk after RFA. Spontaneous release was 〈 2% of maximum release in all experiments. CONCLUSION： Patients with primary and secondary tumors of the liver show a significant tumor-specific cytotoxic T-cell stimulation with a dramatically increased tumor specific cytolytic activity of CD8^＋ T cells after RFA.
