文章：

靶向新抗原增强抗肿瘤免疫

Targeting neoantigens to augment antitumour immunity

原文发布日期：2017-02-24

DOI: 10.1038/nrc.2016.154

类型: Review Article

开放获取: 否

要点：

1. Somatic mutations can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). In the subset of human tumours with a viral aetiology, the proteins encoded by viral genes are another type of neoantigen.
2. Neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. Therefore, neoantigen-specific therapies may be more effective and less toxic than therapies targeting tumour-associated antigens.
3. Neoantigens serve a crucial role in the naturally occurring antitumour T cell response, and are also the most important tumour antigens in certain cancers for which immune checkpoint inhibitors have shown clinical efficacy.
4. As neoantigens are unique and not shared between different patients, neoantigen-targeted therapy will probably need to be on an individual basis. A personalized approach to targeting neoantigens has only recently been possible as a result of major advances in genomics and bioinformatics, including massively parallel sequencing and epitope prediction algorithms.
5. Two therapeutic platforms that could be used to target neoantigens are adoptive cell therapy (ACT) using neoantigen-specific T cell products, and personalized vaccines encoding predicted neoantigens.
6. Neoantigen-specific therapies will probably need to be combined with other therapies such as immune checkpoint inhibitors to overcome immunosuppressive mechanisms in the tumour microenvironment that inhibit neoantigen-specific immune responses.

要点翻译：

1. 体细胞突变可导致肿瘤表达正常细胞上不表达的肿瘤特异性突变蛋白（新抗原）。在具有病毒病因学的人类肿瘤亚群中，病毒基因编码的蛋白质是另一种新抗原。
2. 新抗原因其在肿瘤上的选择性表达可最大程度减少免疫耐受及自身免疫风险，故而成为极具吸引力的免疫靶点。因此，靶向新抗原的疗法可能比靶向肿瘤相关抗原的疗法更有效且毒性更低。
3. 新抗原在自然发生的抗肿瘤T细胞反应中起关键作用，且在免疫检查点抑制剂已显示临床疗效的特定癌症中是最重要的肿瘤抗原。
4. 由于新抗原具有独特性且不同患者间不共享，靶向新抗原的治疗很可能需要个体化方案。得益于基因组学和生物信息学的重大进展（包括大规模平行测序和表位预测算法），针对新抗原的个性化治疗方法直到最近才成为可能。
5. 可用于靶向新抗原的两个治疗平台包括：采用新抗原特异性T细胞产品的过继性细胞疗法（ACT），以及编码预测新抗原的个性化疫苗。
6. 新抗原特异性疗法很可能需要与免疫检查点抑制剂等其他疗法联合使用，以克服肿瘤微环境中抑制新抗原特异性免疫反应的免疫抑制机制。

英文摘要：

The past decade of cancer research has been marked by a growing appreciation of the role of immunity in cancer. Mutations in the tumour genome can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). These neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. In this Review we discuss the emerging evidence that neoantigens are recognized by the immune system and can be targeted to increase antitumour immunity. We also provide a framework for personalized cancer immunotherapy through the identification and selective targeting of individual tumour neoantigens, and present the potential benefits and obstacles to this approach of targeted immunotherapy.

摘要翻译： 

过去十年的癌症研究越来越认识到免疫在癌症中的作用。肿瘤基因组的突变可导致肿瘤表达仅在肿瘤中存在、而正常细胞不表达的突变蛋白（新抗原）。这些新抗原是极具吸引力的免疫靶点，因为它们在肿瘤上的选择性表达可能减少免疫耐受并降低自身免疫风险。在本综述中，我们讨论了新兴证据表明新抗原可被免疫系统识别，并可作为靶点以增强抗肿瘤免疫。我们还提出了通过识别并选择性靶向个体肿瘤新抗原来实现个性化癌症免疫治疗的框架，并阐述了这种靶向免疫治疗方法的潜在益处与障碍。

原文链接：

Targeting neoantigens to augment antitumour immunity