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OBJECTIVE@#To investigate whether interleukin-12 (IL-12) over-expression in malignant melanoma B16 cells affects the expression level of programmed death-1 (PD-1) on T cells in mice during immune microenvironment reconstruction.@*METHODS@#B16 cells were transfected with an IL-12 expression lentiviral vector, and IL-12 over-expression in the cells was verified qPCR and ELISA. Plate cloning assay was used to compare the cell proliferation activity between B16 cells and B16/IL-12 cells. The expression of IL-12 protein in B16/IL-12 cells-derived tumor tissue were detected by ELISA. C57BL/6 mice were inoculated with B16 cells or B16/IL-12 cells, and 14 days later the proportion of T cells with high expression of PD-1 in the tumor-draining lymph nodes was detected by flow cytometry. Mouse models of immune reconstitution established by 650 cGy X-ray radiation were inoculated with B16 (B16+RT group) or B16/IL-12 (B16/IL-12+RT group) cells, with the mice without X-ray radiation prior to B16 cell inoculation as controls. Tumor growth in the mice was recorded at different time points, and on day 14, flow cytometry was performed to detect the proportion of T cells with high PD-1 expression in the tumor-draining lymph nodes and in the tumor tissue.@*RESULTS@#B16 cells infected with the IL-12-overexpressing lentiviral vector showed significantly increased mRNA and protein levels of IL-12 ( < 0.001) without obvious changes in cell viability (>0.05). B16/IL-12 cells expressed higher levels of IL-12 than B16 cells ( < 0.01). In the tumor-bearing mouse models, the proportion of CD4 PD-1 T cells was significantly lower in B16/IL-12 group than in B16 group ( < 0.01). In the mice with X-ray radiation-induced immune reconstitution, PD-1 expressions on CD4 T cells ( < 0.05) and CD8+ T cells ( < 0.01) were significantly higher in B16+ RT group than in the control mice and in B16/IL-12+RT group ( < 0.01 or 0.001); the tumors grew more slowly in B16/IL-12+RT group than in B16 + RT group ( < 0.001).@*CONCLUSIONS@#During immune microenvironment reconstruction, overexpression IL-12 in the tumor microenvironment can reduce the percentage of PD-1 T cells and suppress the growth of malignant melanoma in mice.
Subject(s)
Animals , Mice , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Immune Reconstitution , Interleukin-12 , Melanoma, Experimental , Mice, Inbred C57BL , Tumor MicroenvironmentABSTRACT
Generally speaking,the organism can maintain the stability of T cells.The lymphopeniainduced homeostatic proliferation of T cells could be driven by the recognition of autoantigen including tumor antigen in the absence of foreign antigens or inflammatory signals.This process can break tumor-induced immune tolerance and induce a powerful antitumor immunity.It is confirmed that some negative immune molecules are recruited during the homeostatic proliferation,then the antitumor immunity will be impaired.
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With the further researches on the immune mechanisms in tumor,more and more scholars notice the phenomenon that radiation activates the immunity,and find that radiotherapy causes immunity suppression is one-sided.Although body's anti-tumor immunity can be enhanced by radiotherapy,in clinical,we observe that patients who receive radiotherapy cannot avoid tumor recurrence and metastasis.Researches show that tumor microenvironment makes the immune checkpoint pathway abnormally activated.Therefore,the combination of radiotherapy and immune checkpoint inhibitor can change the tumor microenvironment,and can improve the therapeutic effect.
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<p><b>BACKGROUND</b>It is uncertain that the effect of multimodality treatment with operation on survival for locally advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the effect of multimodality treatment with or without operation on survival for locally advanced NSCLC.</p><p><b>METHODS</b>From May 1992 to May 1999, 114 patients with locally advanced NSCLC were divided into two arms. Arm A (n=56): 39 cases were at stage IIIA, and 17 at stage IIIB; Median KPS was 80 (range from 70 to 90 ); Multimodality treatment program included operation, chemotherapy, radiotherapy and traditional Chinese herb medicine. Of them, lobectomy plus mediastinal systematic lymph node dissection or lymph node sampling accounted for 49 cases, sleeve lobectomy plus mediastinal lymph node dissection for 5 cases, and pneumonectomy for 2 cases. Preoperative or adjuvant chemotherapy regimens included MVP (mitomycin C, vindesine, cisplatin), NP (vinorelbine, cisplatin), TC (paclitaxel, carboplatin), GP (gemcitabine, cisplatin), which were repeated every 4 weeks for 4-6 cycles. Total dose of radiotherapy for lesions in the lung or mediastinal field was 5000-6000cGy. Arm B (n=58): 23 cases were at stage IIIA, and 35 at stage IIIB; Median KPS was 70 (range from 60 to 90); Treatment program was the same approximately as arm A except for no operation.</p><p><b>RESULTS</b>Arm A: (1) Metastatic locations in follow-up, in turn, showed as: lymph node, pleural-lung, bone, brain, liver, pericardium, skin and adrenal; (2) Median survival was 27 months, and 1-, 2- and 5-year survival rate was 82.1%, 60.7% and 25.0% respectively. Arm B: (1) Metastatic locations in follow-up, in turn, showed as: lymph node, pleural-lung, bone, brain, liver, pericardium, skin, adrenal, pancreatic and esophageal metastasis; (2) Median survival was 13 months, and 1-, 2- and 5-year survival rate was 53.4%, 31.0% and 1.7% respectively. Median survival duration of Arm A was significantly superior to Arm B (P=0.0001). There were significant differences in 1-, 2- and 5-year survival rate between the two groups (Chi-Square=9.4, P < 0.01; Chi-Square=8.9, P < 0.01;Chi-Square=11.5, P < 0.01).</p><p><b>CONCLUSIONS</b>Compared with non-operative multimodality treatment, operative multimodality treatment including lobectomy or pneumonectomy with mediastinal lymph node dissection can remarkably improve the survival in patients with locally advanced NSCLC.</p>
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Objective To investigate the relationship between gallbladder carcinoma (GBC) and anomalous arrangement of pancreaticobiliary ductal system (AAPB) through studying the proliferation of gallbladder epithelial cells. Methods ABC Immunohistochemical staining was employed. Results Ki 67 And proliferating cell nuclear antigen PCNA labeling indexes of the non cancerous mucosa in the patients with AAPB and GBC were significantly higher than those in patients with GBC alone (P