• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

硝基化通用T细胞表位疫苗CD47-NitraTh的设计与抑瘤活性

罗建华, 夏雪霏, 姚文兵, 田浤

罗建华, 夏雪霏, 姚文兵, 田浤. 硝基化通用T细胞表位疫苗CD47-NitraTh的设计与抑瘤活性[J]. 中国药科大学学报, 2019, 50(5): 614-621. DOI: 10.11665/j.issn.1000-5048.20190516
引用本文: 罗建华, 夏雪霏, 姚文兵, 田浤. 硝基化通用T细胞表位疫苗CD47-NitraTh的设计与抑瘤活性[J]. 中国药科大学学报, 2019, 50(5): 614-621. DOI: 10.11665/j.issn.1000-5048.20190516
LUO Jianhua, XIA Xuefei, YAO Wenbing, TIAN Hong. Design and antitumor effect of nitrated T helper cell epitope vaccine CD47-NitraTh[J]. Journal of China Pharmaceutical University, 2019, 50(5): 614-621. DOI: 10.11665/j.issn.1000-5048.20190516
Citation: LUO Jianhua, XIA Xuefei, YAO Wenbing, TIAN Hong. Design and antitumor effect of nitrated T helper cell epitope vaccine CD47-NitraTh[J]. Journal of China Pharmaceutical University, 2019, 50(5): 614-621. DOI: 10.11665/j.issn.1000-5048.20190516

硝基化通用T细胞表位疫苗CD47-NitraTh的设计与抑瘤活性

基金项目: 国家自然科学基金资助项目(No.81573335,No.81673343,No.91753112)

Design and antitumor effect of nitrated T helper cell epitope vaccine CD47-NitraTh

  • 摘要: 利用遗传密码扩充技术,将免疫原性氨基酸对硝基苯丙氨酸定点引入到通用T细胞表位,并将其与免疫检查点分子CD47分子胞外区19-140片段融合表达,构建了靶向免疫检查点CD47的疫苗CD47-NitraTh。CD47-NitraTh能够在BALB/c小鼠体内诱导产生高滴度抗体,并可显著抑制CT26结肠癌肿瘤生长,提高脾脏CD4+T细胞和CD8+T细胞的比例,同时可促进naï;ve T细胞向Th1细胞极化。值得关注的是,CD47-NitraTh不仅提高了肿瘤浸润淋巴细胞的比例,同时还降低了肿瘤组织中Treg细胞比例,意味着CD47-NitraTh疫苗能够重塑肿瘤免疫抑制性微环境。本研究结果提示,CD47-NitraTh 可以作为有效的肿瘤疫苗候选分子。
    Abstract: Using the genetic code extension technology, the immunogenic amino acid, p-nitrophenylalanine, was introduced into the universal T cell epitope and then fused with the fragment of the extracellular region of the immune checkpoint molecular CD47(19-140)to construct a vaccine targeting CD47. The CD47-NitraTh vaccine elicited high titer antibody in BALB/c mice, significantly inhibited CT26 colon cancer cells growth, and increased the ratio of spleen CD4+ T cells and CD8+ T cells. Meanwhile, it promoted the polarization of naï ve T cells to Th1 cells. Notably, CD47-NitraTh not only increased the proportion of tumour-infiltrating lymphocytes but also reduced the proportion of Treg cells in tumour tissues, which means that CD47-NitraTh vaccine can remodel the tumour immunosuppressive microenvironment. The results of this study suggested that CD47-NitraTh can be used as an effective tumour vaccine candidate.
  • [1] Betancur PA, Abraham BJ, Yiu YY, et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer[J].Nat Commun,2017,8:14802.
    [2] Matlung HL,Szilagyi K,Barclay NA,et al.The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer[J].Immunol Rev,2017,276(1):145-164.
    [3] Ingram JR,Blomberg OS,Sockolosky JT,et al.Localized CD47 blockade enhances immunotherapy for murine melanoma[J].Proc Natl Acad Sci U S A,2017,114(38):10184-10189.
    [4] Zhang L, Huang H. Targeting the cancer biomarker CD47: a review on the diverse mechanisms of the CD47 pathway in cancer treatment[J].Anticancer Agents Med Chem,2016,16(6):658-667.
    [5] Advani R, Flinn I, Popplewell L, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin′s lymphoma[J].N Engl J Med,2018,379(18):1711-1721.
    [6] Gholamin S,Mitra SS,Feroze AH,et al.Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors[J].Sci Transl Med,2017,9(381):eaaf2968.
    [7] Wong KK,Li WA,Mooney DJ,et al.Advances in therapeutic cancer vaccines[J].Adv Immunol,2016,130:191-249.
    [8] Salman B,Zhou DE,Jaffee EM,et al.Vaccine therapy for pancreatic cancer[J].Oncoimmunology,2013,2(12):e26662.
    [9] Tabi Z,Man S.Challenges for cancer vaccine development[J].Adv Drug Deliv Rev,2006,58(8):902-915.
    [10] He Y,Tian H,Dai X,et al.Immunogenicity of HER2 vaccine containing p-nitrophenylalanine[J].J China Pharm Univ(中国药科大学学报),2018,49(3):369-375.
    [11] Tian H,He Y,Song XD,et al.Nitrated T helper cell epitopes enhance the immunogenicity of HER2 vaccine and induce anti-tumor immunity[J].Cancer Lett,2018,430:79-87.
    [12] Alexander J,Sidney J,Southwood S,et al.Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides[J].Immunity,1994,1(9):751-761.
    [13] Dokmanovic M,Wu WJ.Monitoring trastuzumab resistance and cardiotoxicity:A tale of personalized medicine[J].Adv Clin Chem,2015,70:95-130.
    [14] Gulley JL,Drake CG.Immunotherapy for prostate cancer:recent advances,lessons learned,and areas for further research[J].Clin Cancer Res,2011,17(12):3884-3891.
    [15] Sonpavde G,Agarwal N,Choueiri TK,et al.Recent advances in immunotherapy for the treatment of prostate cancer[J].Expert Opin Biol Ther,2011,11(8):997-1009.
    [16] Grivennikov SI,Greten FR,Karin M.Immunity,inflammation,and cancer[J].Cell,2010,140(6):883-899.
    [17] Datta J,Fracol M,McMillan MT,et al.Association of depressed anti-HER2 T-helper type 1 response with recurrence in patients with completely treated HER2-positive breast cancer:role for immune monitoring[J].JAMA Oncol,2016,2(2):242-246.
    [18] Bos R, Sherman LA. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes[J].Cancer Res,2010,70(21):8368-8377.
    [19] Mlecnik B,Bindea G,Kirilovsky A,et al.The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis[J].Sci Transl Med,2016,8(327):327ra26.
    [20] Facciabene A,Motz GT,Coukos G.T-regulatory cells:key players in tumor immune escape and angiogenesis[J].Cancer Res,2012,72(9):2162-2171.
    [21] Valzasina B, Piconese S, Guiducci C, et al. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25-lymphocytes is Thymus and proliferation independent[J].Cancer Res,2006,66(8):4488-4495.
计量
  • 文章访问数:  485
  • HTML全文浏览量:  0
  • PDF下载量:  816
  • 被引次数: 0
出版历程
  • 刊出日期:  2019-10-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭