Immunogenic neoantigens derived from gene fusions stimulate T cell responses
Immunogenic neoantigens derived from gene fusions stimulate T cell responses
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DOI：
10.1038/s41591-019-0434-2
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发表时间：
2019-05-01
期刊：
影响因子：
82.9
通讯作者：
Morris, Luc G. T.
中科院分区：
文献类型：
--
作者：
Yang, Wei;Lee, Ken-Wing;Morris, Luc G. T.
抗肿瘤免疫是由自我歧视和非自我歧视驱动的。许多癌症的免疫治疗方法都利用了来自体细胞突变的肿瘤新抗原。在这里，我们证明了基因融合是免疫原性新抗原的来源，可以介导对免疫治疗的反应。我们确定了一名对转移性头颈部癌症有特殊反应的患者，他对免疫检查点抑制剂治疗完全有效，尽管突变负荷较低，治疗前肿瘤中的免疫渗透最少。利用全基因组测序和RNA测序，我们鉴定了一种新的基因融合，并证明它产生了一种新的抗原，可以特异性地诱导宿主细胞毒性T细胞反应。在一组突变负担低、免疫渗透最少和普遍存在基因融合的头颈部肿瘤中，我们还发现了能产生细胞毒性T细胞反应的基因融合衍生新抗原。最后，分析融合阳性癌症的其他数据集，包括检查点抑制剂治疗的肿瘤，我们发现了免疫监视导致对融合基因衍生新抗原的负选择压力的证据。这些发现突出了一类重要的肿瘤特异性抗原，并对靶向基因融合事件具有意义，否则癌症对免疫治疗的反应较差，包括低突变负荷和最低免疫渗透的癌症。
Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.