Publications (5)13.53 Total impact
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Article: [Effect of HPV16 peptide vaccine in combination with paclitaxel-cisplatin chemotherapy on cervical cancer in vitro and in vivo].
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ABSTRACT: to the explore the effect of Human papillomavirus (HPV) 16 peptide vaccine in combination with paclitaxel-cisplatin (TP) chemotherapy on cervical cancer in vitro and in vivo. (1) the major histocompatibility complex (MHC) class I restricted T cell epitopes were studied by bioinformatics for transporter associated with antigen processing (TAP). Their effects were compared and E7Pa had the most dramatic effect. (2) In vivo, the C57BL/6 mice were divided equally into 6 groups randomly after loading with TC-1 cells (HPV 16 positive tumor cells from C57BL/6 mouse), named as E7Pa + CpG + TP, E7Pa + CpG, CpG + TP, TP and CpG group as experiment groups and control (blank injection with physiological saline). The tumor volumes were measured regularly by tumor growth curve to compare the therapeutic effects in different groups; the related cell factors in murine peripheral blood were evaluated by enzyme-linked immunosorbent assay (ELISA); the TUNEL test kit was used to explore cellular apoptosis in tumor tissue; the survival curve was drawn from the TC-1 cell loading to natural death; safety was tested by pathological test and leucocyte count. at day 60 of tumor growth, the tumor volume of immunotherapy plus TP chemotherapy group was (0.013 ± 0.010) cm(3) versus the control (1.900 ± 0.075) cm(3) with a great significant deviation (P < 0.01). Meanwhile, the volumes were E7Pa + CpG group (0.340 ± 0.038) cm(3), TP + CpG group (0.650 ± 0.029) cm(3), TP group (1.100 ± 0.052) cm(3) and that of CpG group was (0.890 ± 0.047) cm(3) separately. And these groups had significant difference with the controls (P < 0.05). The average survival time of different groups were E7Pa + CpG + TP group (108.50 ± 8.97) d, E7Pa + CpG group (100.02 ± 2.27) d, CpG + TP group (79.63 ± 4.05) d, TP group (73.24 ± 3.11) d, CpG group (68.63 ± 1.38) d and controls (52.37 ± 2.47) d. And the difference between the E7Pa + CpG + TP and E7Pa + CpG groups had great significance with the controls (P < 0.01). Furthermore, the immune system was effectively stimulated for suppressing tumor growth in the immunotherapy group while cell apoptosis was significantly induced in the chemotherapy group. The combination of immunotherapy and chemotherapy was significantly efficacious than either of them alone. And it could thoroughly stimulate the immune effects and enhance the anti-tumor function of chemotherapeutical drugs. In safety test, there was no significant difference among all groups. the HPV16 peptide vaccine in combination with TP chemotherapy can treat the HPV16 E7 positive tumor effectively in experiment.Zhonghua yi xue za zhi 11/2010; 90(43):3035-9. -
Article: [Therapeutic effects of B and T lymphocyte attenuator extracellular domain and heat shock protein 70 antigen peptide on cervical cancer in mouse model].
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ABSTRACT: To investigate the synergistic therapy effects of B and T lymphocyte attenuator (BTLA) extracellular domain in combination with heat shock protein 70 (HSP70)-TC-1 antigen peptide complex on the mouse model of cervical cancer and the related immunological mechanisms. (1) Detecting the BTLA and herpesvirus entry mediator (HVEM) gene expression in the tumor microenvironment after C57BL/6 mice were inoculated with TC-1 tumor cells by realtime PCR; BTLA, HVEM expression on tumor infiltrating lymphocytes cell surface were detected by flow cytometry (fluorescence intensity). (2) According to different treatments, tumor-bearing mice were divided into 5 groups, which was injected with pcDNA3.1 (empty vector plasmid as control), psBTLA (vector plasmid which expresses BTLA extracellular domain), HSP70 (HSP70-TC-1 cell peptide complex), HSP70 + pcDNA3.1 or HSP70 + psBTLA, respectively. The weight of tumor was recorded. The expression of immunoregulatory genes in tumor microenvironment were detected. The change of lymphocyte amount and cytotoxicity were detected too; lymphocyte proliferation activity was measured by tritium thymidine incorporation assay; the concentration of interleukin (IL)2 and interferon-γ (IFN-γ) in supernatants of spleen lymphocyte were measured by enzyme-linked immunosorbent assay (ELISA). (1) BTLA gene expression was gradually increased after tumor cells inoculation. The highest expression level was 2.83 ± 0.35 at 14th day, which had statistical significance difference with the 7th day expression of 1.66 ± 0.25 (P < 0.05). While HVEM mRNA expression did not change significantly (P > 0.05). The 7th and 14th day after TC-1 cells inoculation, the average fluorescence intensity of BTLA expression on the surface of tumor infiltrating lymphocytes was 33.5 and 51.8, respectively, in which there was statistically significant difference (P < 0.05); while the difference of HVEM expression was not statistically significant (57.2 vs 49.3, P > 0.05). (2) The 28th day after inoculation, tumor inhibition rate of HSP70 + psBTLA group was 88%, which was significantly higher than other treatment groups (P < 0.05). The 28th day after TC-1 cells inoculation, combination therapy not only promoted IFN-γ and IL-2 gene (3.12 ± 0.71, 3.20 ± 0.62) expression but also reduced transforming growth factor-β (TGF-β), Foxp3 and IL-10 expression (0.25 ± 0.03, 0.19 ± 0.03, 0.31 ± 0.04; P < 0.05). It also promoted CD₈(+) T lymphocyte infiltration (52 ± 6)/high power field, cytotoxicity (65.5 ± 2.4)%, proliferation (15.0 × 10³ cpm) and cytokine IL-2, IFN-γ secretion (824 ± 51), (1096 ± 112) pg/ml, which were all significantly higher than other groups (P < 0.05). The effect of immunotherapy on tumor can be augmented by the combination of psBTLA which expresses extracellular domain of BTLA and HSP70-TC-1 tumor antigen peptide complex, which could improve the expression of the related immunoregulatory genes to establish a much better microenvironment in favor of anti-tumor immune response against the mice model of the cervix carcinoma.Zhonghua fu chan ke za zhi 08/2010; 45(8):603-8. -
Article: [Preparation of human papillomavirus 16 E7 peptide vaccine and its effectiveness in vitro and in vivo.].
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ABSTRACT: To prepare the human papillomavirus (HPV) 16 peptide vaccine and explore the effect in vitro and in vivo. (1) Prediction of the major histocompatibility complex (MHC) class I restricted T cell epitopes by bioinformatics target at transporter associated with antigen processing (TAP) and named by E7Pa, E7Pb, E7Pc separately. (2) In vivo, the C57BL/6 mice were divided into five groups with same amounts randomly after loading with TC-1 cells (HPV 16 positive tumor cells from C57BL/6 mouse), named as E7Pa + CpG, E7Pb + CpG, E7Pc + CpG (as experiment groups, and added 50 microg/ml E7Pa, E7Pb, E7Pc, respectively), CpG (as positive control group and added Con A with 12 mg/L final concentration) and blank control group (without any treatment). The T cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay at different time points; the lactate dehydrogenase (LDH) delivery method was used to test the cytolytic T lymphocyte (CTL) activity of mouse splenic lymphocyte in different ratio of effector cells and target cells (E:T); the related cytokines in tumor tissue and mouse peripheral blood were evaluated by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. The tumor volumes were measured to contrast the therapeutic effect in different groups. (1) Three peptide named E7Pa, E7Pb, E7Pc were successfully preparated which had high affinity and specificity. (2) After vaccination of 24, 48, 72, 96 hours, MTT results shown that the proliferation rate in E7Pa + CpG group were (131 +/- 32)%, (302 +/- 15)%, (552 +/- 28)%, (731 +/- 24)% individually, which were much higher than those in blank control [(72 +/- 15)%, (120 +/- 57)%, (176 +/- 41)%, (288 +/- 29)%; P < 0.01], and the other groups i.e. E7Pb + CpG, E7Pc + CpG and CpG groups all proliferated much higher than those in blank control group with statistic signification (P < 0.05), but there was no significant difference between groups (P > 0.05); the LDH delivery assay showed that when the ratio of E:T was 100:1, the activity of CTL in the E7Pa + CpG group was most powerful than the other groups with statistic signification (P < 0.01).Meanwhile, the ratio of E:T was concentration-dependent. Compared E7Pb + CpG, E7Pc + CpG or CpG groups with blank control group, there were significantly difference (P < 0.05), while there was no significant difference between groups (P > 0.05). The mRNA levels of interferon gamma (IFN-gamma), interleukin-2 (IL-2) in tumor tissue and peripheral blood in E7Pa + CpG group were significantly higher than those in blank control group (P < 0.01), which was the similar results when compared E7Pb + CpG, E7Pc + CpG or CpG groups with control group (P < 0.05), and without significant difference between groups (P > 0.05). The tumor volumes were suppressed obviously in all the experiment groups, especially at the 60th days, the volumes in E7Pa + CpG group were much smaller than that in blank control group with statistic signification (P < 0.01), which was the similar results that E7Pb + CpG, E7Pc + CpG or CpG groups had difference than blank control group with statistic signification (P < 0.05), and without significant difference between groups (P > 0.05). The HPV16 E7 peptide target at TAP combination with CpG as a vaccine could treat effectively the HPV16 E7 positive tumor in experiment.Zhonghua fu chan ke za zhi 12/2009; 44(12):903-8. -
Article: Soluble PD-1 facilitates 4-1BBL-triggered antitumor immunity against murine H22 hepatocarcinoma in vivo.
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ABSTRACT: The use of costimulatory molecules targeting distinct T-cell signaling pathways has provided a means for triggering and enhancing antitumor immunity; however, it is still not fully understood what types of costimulatory molecules are suitable for the combination in tumor therapy. Our purpose in this study is to establish an effective antitumor immune approach by using costimulatory molecule 4-1BBL in combination with soluble PD-1. The murine H22 hepatocarcinoma served as an ectopic tumor model. Local gene transfer was done by injection with naked plasmid p4-1BBL and/or psPD-1. The synergistic mechanism of dual-gene therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment. The effects of immunotherapy were evaluated by testing the function of tumor-specific T cells, measuring tumor weight or volume, survival of mice, and H&E staining of tissues. 4-1BBL expressed by normal nonimmune cells effectively enhanced antitumor immune response but up-regulated PD-L1 and did not reduce IL-10 and transforming growth factor-beta (TGF-beta). sPD-1 synergized with 4-1BBL to establish efficient antitumor immune environment, including down-regulation of IL-10 and TGF-beta, further up-regulation of interleukin (IL)-2 and IFN-gamma, and higher CD8(+) T-cell infiltration. The combined treatment by 4-1BBL/sPD-1 eradicated tumors from mice with small amounts of preexistent tumor cells or tumors from approximately 60% of individuals with larger amounts of preexistent tumor cells. Our findings in this report imply a great potential of 4-1BBL in combination with sPD-1 in tumor therapeutics with the in vivo existent tumor cells as antigens.Clinical Cancer Research 03/2007; 13(6):1823-30. · 7.74 Impact Factor -
Article: Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cell-mediated immune response.
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ABSTRACT: T cell Ig mucin 3 (Tim-3) has been found to play an important role in Th1-mediated auto- and alloimmune responses, but the function of soluble form of Tim-3 (sTim-3) remains to be elucidated. In this study, we report the inhibitory effect of sTim-3 on T cell-mediated immune response. In this study, sTim-3 mRNA was found, among different tissues and organs, only in splenic cells, and the activation of splenocytes resulted in up-regulated production of both sTim-3 mRNA and protein. We constructed a eukaryotic expression plasmid, psTim-3, which expresses functional murine sTim-3. In C57BL/6 mice inoculated with B16F1 melanoma cells, the growth of tumor was facilitated by the expression of this plasmid in vivo. Furthermore, sTim-3 inhibited the responses of T cells to Ag-specific stimulation or anti-CD3 mAb plus anti-CD28 mAb costimulation and the production of cytokines IL-2 and IFN-gamma in vitro. In tumor rejection model, sTim-3 significantly impaired T cell antitumor immunity, evidenced by decreased antitumor CTL activity and reduced amount of tumor-infiltrating lymphocytes in tumor. Real-time PCR analysis of gene expression in tumor microenvironment revealed the decreased expression of Th1 cytokine genes and the unchanged profile of the genes related to T regulatory cell function, suggesting that the inhibitory effect of sTim-3 on the generation of Ag-specific T cells in vivo is dominated by T effector cells rather than T regulatory cells. Our studies thus define sTim-3 as an immunoregulatory molecule that may be involved in the negative regulation of T cell-mediated immune response.The Journal of Immunology 03/2006; 176(3):1411-20. · 5.79 Impact Factor
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Institutions
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2010
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Tongji University
- Shanghai First Maternity and Infant Health Hospital
Shanghai, Shanghai Shi, China
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2009–2010
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Tongji Hospital
Wuhan, Hubei, China
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