• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Mutant MHC class II epitopes drive therapeutic immune responses to cancer
【24h】

Mutant MHC class II epitopes drive therapeutic immune responses to cancer

机译：突变的MHC II类表位驱动对癌症的治疗性免疫反应

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations (the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutationsl. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by Cal+ T cells. Vaccination with such Cal+ immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that Cal+ T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.
机译：肿瘤特异性突变是癌症免疫治疗的理想靶标，因为它们在健康组织中缺乏表达，并且可能被成熟的T细胞库识别为新抗原。但是，由于每个患者的肿瘤都有一组独特的突变（突变组），因此必须通过疫苗方法对它们进行系统靶向，这一事实必须首先加以鉴定。最近，我们提出了一种个性化的免疫治疗方法，以针对患者个体肿瘤特异性突变的全谱为目标。在这里，我们在三个独立的鼠类肿瘤模型中显示，相当一部分非同义的癌症突变具有免疫原性，而且出乎意料的是，大多数免疫原性突变组都被Cal + T细胞识别。此类Cal +免疫原性突变的疫苗接种具有强大的抗肿瘤活性。受这些发现的鼓舞，我们建立了一个流程，通过该流程，可以仅通过生物信息学优先级选择外显子组测序鉴定出的突变作为疫苗靶标，这些表达水平取决于其表达水平和主要的组织相容性复合物（MHC）II类结合能力，可快速合成生产多新表位信使RNA疫苗。我们显示，用这种多表位mRNA疫苗进行的疫苗接种可诱导有效的肿瘤控制，并完全排斥小鼠中已建立的侵袭性生长的肿瘤。此外，我们证明，Cal + T细胞新表位疫苗接种可重塑肿瘤微环境，并诱导小鼠针对独立免疫优势抗原的细胞毒性T淋巴细胞反应，表明抗原扩散的编排。最后，我们通过对相应的人类癌症类型采用相同的预测算法，证明了丰富的突变有望与人类MHC II类结合。因此，这里介绍的量身定制的免疫治疗方法可以被认为是全面利用实质性新表位靶标癌症的普遍适用的蓝图，从而能够利用“及时”生产的疫苗有效地靶向每个患者的肿瘤。

著录项

  • 来源
    《Nature》 |2015年第7549期|692-696|共5页
  • 作者

    Kreiter Sebastian; Vormehr Mathias; van de Roemer Niels; Diken Mustafa; Loewer Martin; Diekmann Jan; Boegel Sebastian; Schroers Barbara; Vascotto Fulvia; Castle John C.; Tadmor Arbel D.; Schoenberger Stephen P.; Huber Christoph; Tuereci Oezlem; Sahin Ugur;

  • 作者单位

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Res Ctr Immunotherapy FZI, D-55131 Mainz, Germany;

    Res Ctr Immunotherapy FZI, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany|Biopharmaceut New Technol BioNTech Corp, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA;

    Res Ctr Immunotherapy FZI, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany;

    Johannes Gutenberg Univ Mainz, Univ Med Ctr, TRON Translat Oncol, D-55131 Mainz, Germany|Res Ctr Immunotherapy FZI, D-55131 Mainz, Germany|Biopharmaceut New Technol BioNTech Corp, D-55131 Mainz, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号