Pan-cancer deconvolution of tumour composition using DNA methylation
Pan-cancer deconvolution of tumour composition using DNA methylation
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DOI：
10.1038/s41467-018-05570-1
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发表时间：
2018-08-13
影响因子：
16.6
通讯作者：
Fenton, Tim R.
中科院分区：
文献类型：
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作者：
Chakravarthy, Ankur;Furness, Andrew;Fenton, Tim R.
实体瘤中免疫细胞浸润的性质和程度是治疗反应的关键决定因素。在这里，使用基于DNA甲基化的肿瘤细胞分数去卷积方法，我们报告了广泛的实体癌中肿瘤组成和基因组学的综合分析。最初研究头颈部鳞状细胞癌，我们确定了两个不同的肿瘤亚组：“免疫热”和“免疫冷”，这显示出不同的预后，突变负荷，细胞因子信号传导，细胞溶解活性和致癌驱动事件。我们证明了存在这样的肿瘤亚组泛癌，链接克隆新抗原负荷细胞毒性T淋巴细胞浸润，并显示热肿瘤的转录签名选择性地参与免疫治疗应答者。我们还发现，未经治疗的热肿瘤明显富含已知的免疫耐药基因组改变，这可能解释了该组中免疫治疗反应和预后的异质性。最后，我们定义了主动抗肿瘤免疫介质的目录，推导出候选生物标志物和精确免疫治疗的潜在靶点。
The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: 'immune hot' and 'immune cold', which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy.