BACKGROUND The tumor microenvironment can be classified into immunologically active "inflamed" tumors and inactive "non-inflamed" tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy. METHODS We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing. FINDINGS Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells. INTERPRETATION Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer. FUNDING The Japan Agency for Medical Research and Development (AMED).

中文翻译：

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原发性肝癌的分类与免疫抑制机制及其与基因组改变的相关性。

背景技术根据细胞毒性免疫细胞的浸润，肿瘤微环境可分为免疫活性“炎症”肿瘤和非活性“非炎症”肿瘤。先前对肝癌的研究表明，与非炎症肿瘤相比，炎症肿瘤的预后更好。然而，肝癌在免疫学和遗传学上具有高度异质性，对肝癌微环境的更精细分类可能会提高我们对其免疫多样性和对免疫治疗反应的理解。方法 我们使用肿瘤和匹配的非肿瘤性肝炎肝脏的 RNA 测序技术，对来自日本人群的 234 种原发性肝癌（主要与病毒相关）的免疫基因特征进行了表征。然后我们将它们与使用全基因组测序检测到的体细胞改变进行比较。研究结果 肝癌表达的免疫标记基因水平低于非肿瘤性肝炎肝脏，表明肿瘤微环境中存在免疫抑制。几种免疫抑制机制积极且相互排斥地发挥作用，导致肝癌的四种免疫亚类：肿瘤相关巨噬细胞（TAM）、CTNNB1、细胞溶解活性（CYT）和调节性T细胞（Treg）。CYT 和 Treg 亚类代表炎症肿瘤，而 TAM 和 CTNNB1 亚类代表非炎症肿瘤。TAM 亚类占肝癌的 31%，其生存率较差，细胞外基质基因表达水平升高，并且与染色质调节因子 ARID2 的体细胞突变相关。细胞系实验的结果表明 ARID2 与肝癌细胞产生的趋化因子之间存在功能联系。解释 原发性肝癌根据相互排斥的免疫抑制机制分为四个亚类。这一分类表明 TAM 和 Treg 等免疫抑制机制作为肝癌治疗靶点的重要性。资金 日本医学研究开发机构 (AMED)。