Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
EBioMedicine. 2020 Mar;53:102659. doi: 10.1016/j.ebiom.2020.102659. Epub 2020 Feb 26.
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.
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.
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.
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.
The Japan Agency for Medical Research and Development (AMED).
基于细胞毒性免疫细胞浸润情况，肿瘤微环境可分为免疫活跃的“炎症”肿瘤和不活跃的“非炎症”肿瘤。先前的肝癌研究报告称，与非炎症肿瘤相比，炎症肿瘤的预后更好。然而，肝癌在免疫和遗传上具有高度异质性，对肝癌微环境进行更精细的分类可能有助于我们更好地了解其免疫多样性和对免疫治疗的反应。
我们使用来自日本人群的 234 例主要与病毒相关的原发性肝癌肿瘤和配对非肿瘤性肝炎肝的 RNA-Seq 对其免疫基因特征进行了表征。然后，我们将这些特征与全基因组测序检测到的体细胞改变进行了比较。
肝癌表达的免疫标志物基因水平低于非肿瘤性肝炎肝，表明肿瘤微环境存在免疫抑制。几种免疫抑制机制活跃且相互排斥，导致肝癌存在 4 种免疫亚型：肿瘤相关巨噬细胞（TAM）、CTNNB1、细胞毒性（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%，预后不良，表达高水平的细胞外基质基因，与染色质调节因子 ARID2 的体细胞突变相关。细胞系实验结果表明 ARID2 与肝癌细胞产生趋化因子之间存在功能联系。
原发性肝癌可根据免疫抑制的互斥机制分为 4 个亚类。该分类提示了 TAM 和 Treg 等免疫抑制机制作为肝癌治疗靶点的重要性。
日本医疗研究与发展机构（AMED）。
