Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer.
Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer.
复制标题
表观基因组和早期选择决定结直肠癌的肿瘤免疫进化轨迹。
DOI：
10.1101/2024.02.12.579956
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Mi
中科院分区：
文献类型：
--
作者：
Lakatos,Eszter;Gunasri,Vinaya;Zapata,Luis;Househam,Jacob;Heide,Timon;Trahearn,Nicholas;Swinyard,Ottilie;Cisneros,Luis;Lynn,Claire;Mossner,Maximilian;Kimberley,Chris;Spiteri,Inmaculada;Cresswell,GeorgeD;Llibre-Palomar,Gerard;Mi
免疫系统控制是癌症进化必须绕过的一个主要障碍。逃脱免疫控制的亚克隆的相对时间和进化动力学仍然不完全，免疫介导的选择如何塑造表观基因组也很少受到关注。在这里，我们推断基因组和表观基因组驱动的肿瘤免疫协同进化的动力学内原发性结直肠癌（CRC）。我们利用我们现有的CRC多区域多组学数据集，我们补充了高分辨率空间分辨的新抗原测序数据和肿瘤微环境（TME）的高度多重成像。体细胞染色质可及性改变（SCAAs）的分析揭示了抗原呈递基因处的可及性的频繁体细胞损失，并且SCAAs有助于新抗原的沉默。我们观察到，强免疫逃逸和排斥发生在CRC形成的开始，并且在肿瘤内，包括在单个肿瘤腺体的微观水平，额外的免疫逃逸改变对癌细胞的免疫表型具有可忽略的后果。在局部入侵期间发生进一步的轻微免疫编辑，并与TME重组相关，但进化瓶颈相对较弱。总的来说，我们发现CRC中的免疫逃避遵循“大爆炸”进化模式，即在转化时获得的遗传、表观遗传和TME驱动的免疫逃避定义了随后的癌症免疫进化。
Immune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs). We utilise our existing CRC multi-region multi-omic dataset that we supplement with high-resolution spatially-resolved neoantigen sequencing data and highly multiplexed imaging of the tumour microenvironment (TME). Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes, and that SCAAs contribute to silencing of neoantigens. We observe that strong immune escape and exclusion occur at the outset of CRC formation, and that within tumours, including at the microscopic level of individual tumour glands, additional immune escape alterations have negligible consequences for the immunophenotype of cancer cells. Further minor immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak. Collectively, we show that immune evasion in CRC follows a “Big Bang” evolutionary pattern, whereby genetic, epigenetic and TME-driven immune evasion acquired by the time of transformation defines subsequent cancer-immune evolution.