人参皂苷Rg3联合阿帕替尼促进可诱导共刺激分子(ICOS)上调的肺癌细胞免疫应答
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摘要
目的研究人参皂苷Rg3联合阿帕替尼在可诱导共刺激分子(ICOS)上调的肺癌的细胞免疫应答中的作用。方法建立Lewis肺癌小鼠模型后,随机分为8组,将人参皂苷Rg3或/和阿帕替尼联合ICOS激动剂单克隆抗体作用于小鼠体内,观察各组肿瘤生长、肿瘤组织中CD8~+T淋巴细胞富集和细胞因子IFN-γ、IL-4和TNF-α变化,以及其表面ICOS表达情况。结果人参皂苷Rg3和阿帕替尼联合应用,显著增强ICOS激动剂单克隆抗体显著抑制肿瘤的生长;促进CD8~+T淋巴细胞在肿瘤组织中的富集,上调IFN-γ、IL-4和TNF-α分泌;ICOS激动剂单克隆抗体促进CD8~+T淋巴细胞表面的ICOS表达,但其表达量不受Rg3和阿帕替尼的影响。结论人参皂苷Rg3联用阿帕替尼能增强ICOS促进的肺癌模型动物内细胞免疫应答。
The study was performed to investigate the role of ginsenoside Rg3 in combination with apatinib in the cell immune response upregulated by inducible costimulatory molecule ICOS in lung cancer. A Lewis lung cancer model in C57BL/6 mice was established and randomly divided into 8 groups. Ginsenoside Rg3 or/and apatinib combined with ICOS agonist monoclonal antibodies were administered to mice, then we observed the tumor growth and tumor infiltrating CD8~+T cells, the levels of IFN-γ, IL-4 and TNF-α, and the surface ICOS expression of CD8~+T cells in each group. Data showed that the combination of ginsenoside Rg3 and apatinib significantly inhibited tumor growth, enhanced the cell immune response upregulated by ICOS agonist monoclonal antibody through promoting the enrichment of CD8~+T cells and the secretion of cytokines(IFN-γ, IL-4 and TNF-α). While the ICOS agonist monoclonal antibody promoted the the surface ICOS expression of CD8~+T cells, but did not affected by the ginsenoside Rg3 and apatinib. These finding demonstrates that the combination of ginsenoside Rg3 and apatinib can enhance the ICOS-promoted cell immune response in lung cancer model animals.
The study was performed to investigate the role of ginsenoside Rg3 in combination with apatinib in the cell immune response upregulated by inducible costimulatory molecule ICOS in lung cancer. A Lewis lung cancer model in C57BL/6 mice was established and randomly divided into 8 groups. Ginsenoside Rg3 or/and apatinib combined with ICOS agonist monoclonal antibodies were administered to mice, then we observed the tumor growth and tumor infiltrating CD8~+T cells, the levels of IFN-γ, IL-4 and TNF-α, and the surface ICOS expression of CD8~+T cells in each group. Data showed that the combination of ginsenoside Rg3 and apatinib significantly inhibited tumor growth, enhanced the cell immune response upregulated by ICOS agonist monoclonal antibody through promoting the enrichment of CD8~+T cells and the secretion of cytokines(IFN-γ, IL-4 and TNF-α). While the ICOS agonist monoclonal antibody promoted the the surface ICOS expression of CD8~+T cells, but did not affected by the ginsenoside Rg3 and apatinib. These finding demonstrates that the combination of ginsenoside Rg3 and apatinib can enhance the ICOS-promoted cell immune response in lung cancer model animals.
引文
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[14]Joo SS,Yoo YM,Ahn BW,et al.Prevention of inflammation-mediated neurotoxicity by Rg3 and its role in microglial activation[J].Biol Pharm Bull,2008,31(7):1392-1396.
[15]Rivera E,Daggfeldt A,Hu S.Ginseng extract in aluminium hydroxide adjuvanted vaccines improves the antibody response of pigs to porcine parvovirus and Erysipelothrix rhusiopathiae[J].Vet Immunol Immunopathol,2003,91(1):19-27.
[16]Rivera E,Hu S,Concha C.Ginseng and aluminium hydroxide act synergistically as vaccine adjuvants[J].Vaccine,2003,21(11/12):1149-1157.
[17]Hu S,Concha C,Lin F,et al.Adjuvant effect of ginseng extracts on the immune responses to immunisation against Staphylococcus aureus in dairy cattle[J].Vet Immunol Immunopathol,2003,91(1):29-37.
[18]Song X,Chen J,Sakwiwatkul K,et al.Enhancement of immune responses to influenza vaccine(H3N2)by ginsenoside Re[J].Int Immunopharmacol,2010,10(3):351-356.
[19]Zhai L,Li Y,Wang W,et al.Effect of oral administration of ginseng stem-and-leaf saponins(GSLS)on the immune responses to Newcastle disease vaccine in chickens[J].Vaccine,2011,29(31):5007-5014.
[20]Wei X,Chen J,Su F,et al.Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice[J].Int Immunol,2012,24(7):465-471.
[21]Hu X,Zhang J,Xu B,et al.Multicenter phase II study of apatinib,a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer[J].Int J Cancer,2014,135(8):1961-1969.
[22]Song Z,Yu X,Lou G,et al.Salvage treatment with apatinib for advanced non-small-cell lung cancer[J].Onco Targets Ther,2017,10:1821-1825.
[2]宁昕,尹艳慧.肿瘤抗原特异性T细胞受体改造的T细胞研究现状及应用前景[J].免疫学杂志,2018,34(1):65-72.
[3]Amatore F,Gorvel L,Olive D.Inducible co-stimulator(ICOS)as a potential therapeutic target for anti-cancer therapy[J].Expert Opin Ther Targets,2018,22(4):343-351.
[4]Sun M,Ye Y,Xiao L,et al.Anticancer effects of ginsenoside Rg3(Review)[J].Int J Mol Med,2017,39(3):507-518.
[5]安宁,朱文.人参皂苷Rg3抗肿瘤作用机制研究进展[J].现代肿瘤医学,2008,16(4):648-652.
[6]Tian S,Quan H,Xie C,et al.YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo[J].Cancer Sci,2011,102(7):1374-1380.
[7]Li F,Zhu T,Cao B,et al.Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance[J].Eur J Cancer,2017,84:184-192.
[8]Rodrigo Garzón M,Tirapu Fernández de la Cuesta I,Arina Iraeta A,et al.Use of gene therapy in a subcutaneous murine model of lung cancer[J].Arch Bronconeumol,2006,42(10):526-532.
[9]Burugu S,Dancsok AR,Nielsen TO.Emerging targets in cancer immunotherapy[J].Semin Cancer Biol,2017,52(2):39-52.
[10]宋健,高晓燕,范小琴,等.白细胞及其亚类计数揭示肺癌的代偿机制[J].免疫学杂志,2018,34(8):690-695.
[11]Liu CX,Xiao PG.Recent advances on ginseng research in China[J].J Ethnopharmacol,1992,36(1):27-38.
[12]Seong YH,Shin CS,Kim HS,et al.Inhibitory effect of ginseng total saponins on glutamate-induced swelling of cultured astrocytes[J].Biol Pharm Bull,1995,18(12):1776-1778.
[13]Kitts DD,Wijewickreme AN,Hu C.Antioxidant properties of a North American ginseng extract[J].Mol Cell Biochem,2000,203(1/2):1-10.
[14]Joo SS,Yoo YM,Ahn BW,et al.Prevention of inflammation-mediated neurotoxicity by Rg3 and its role in microglial activation[J].Biol Pharm Bull,2008,31(7):1392-1396.
[15]Rivera E,Daggfeldt A,Hu S.Ginseng extract in aluminium hydroxide adjuvanted vaccines improves the antibody response of pigs to porcine parvovirus and Erysipelothrix rhusiopathiae[J].Vet Immunol Immunopathol,2003,91(1):19-27.
[16]Rivera E,Hu S,Concha C.Ginseng and aluminium hydroxide act synergistically as vaccine adjuvants[J].Vaccine,2003,21(11/12):1149-1157.
[17]Hu S,Concha C,Lin F,et al.Adjuvant effect of ginseng extracts on the immune responses to immunisation against Staphylococcus aureus in dairy cattle[J].Vet Immunol Immunopathol,2003,91(1):29-37.
[18]Song X,Chen J,Sakwiwatkul K,et al.Enhancement of immune responses to influenza vaccine(H3N2)by ginsenoside Re[J].Int Immunopharmacol,2010,10(3):351-356.
[19]Zhai L,Li Y,Wang W,et al.Effect of oral administration of ginseng stem-and-leaf saponins(GSLS)on the immune responses to Newcastle disease vaccine in chickens[J].Vaccine,2011,29(31):5007-5014.
[20]Wei X,Chen J,Su F,et al.Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice[J].Int Immunol,2012,24(7):465-471.
[21]Hu X,Zhang J,Xu B,et al.Multicenter phase II study of apatinib,a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer[J].Int J Cancer,2014,135(8):1961-1969.
[22]Song Z,Yu X,Lou G,et al.Salvage treatment with apatinib for advanced non-small-cell lung cancer[J].Onco Targets Ther,2017,10:1821-1825.