Mutant MHC class II epitopes drive therapeutic immune responses to cancer.
Mutant MHC class II epitopes drive therapeutic immune responses to cancer.
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DOI：
10.1038/nature14426
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发表时间：
2015-04-30
期刊：
影响因子：
64.8
通讯作者：
Sahin U
中科院分区：
文献类型：
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作者：
Kreiter S;Vormehr M;van de Roemer N;Diken M;Löwer M;Diekmann J;Boegel S;Schrörs B;Vascotto F;Castle JC;Tadmor AD;Schoenberger SP;Huber C;Türeci Ö;Sahin U
肿瘤特异性突变是癌症免疫治疗的理想靶点，因为它们在健康组织中缺乏表达，并有可能被成熟的T细胞谱系识别为新抗原。然而，由于每个患者的肿瘤都有一组独特的突变(“突变组”)，必须首先识别这些突变，疫苗方法的系统性靶向受到了阻碍。最近，我们提出了一种个性化的免疫治疗方法，以靶向患者个体肿瘤特异性突变的全谱。在这里，我们在三个独立的小鼠肿瘤模型中表明，相当大一部分非同义癌症突变是免疫原性的，而且出人意料的是，大多数免疫原性突变是由CD4+T细胞识别的。接种这种CD4+免疫原性突变的疫苗具有很强的抗肿瘤活性。在这些发现的鼓舞下，我们建立了一个过程，通过外显子组测序确定的突变可以仅通过生物信息学优先排序来选择作为疫苗靶标，基于它们的表达水平和主要组织相容性复合体(MHC)II类结合能力，以快速生产合成多新表位信使RNA疫苗。我们发现，接种这种多表位基因疫苗可以有效地控制肿瘤，并完全排斥小鼠体内已建立的侵袭性生长的肿瘤。此外，我们证明了CD4+T细胞新表位疫苗重塑了肿瘤微环境，并在小鼠中诱导了针对一种独立的免疫优势抗原的细胞毒性T淋巴细胞反应，这表明抗原的传播是协调的。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，证明了在人类癌症中也有大量预测与MHC II类结合的突变。因此，这里介绍的量身定制的免疫治疗方法可以被视为一种普遍适用的蓝图，用于全面开发癌症的大量新表位靶标，使生产的疫苗能够及时有效地靶向每一位患者的肿瘤。
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 mutations. 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 CD4+ T cells. Vaccination with such CD4+ 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 CD4+ 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’.