Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.
Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.
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DOI：
10.1136/gutjnl-2021-325918
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发表时间：
2023-01
期刊：
影响因子：
24.5
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
--
作者：
Montironi, Carla;Castet, Florian;Haber, Philipp K.;Pinyol, Roser;Torres-Martin, Miguel;Fontanals, Laura Torrens;Mesropian, Agavni;Wang, Huan;Puigvehi, Marc;Maeda, Miho;Leow, Wei Qiang;Harrod, Elizabeth;Taik, Patricia;Chinburen, Jigjidsuren;Taivanbaatar, Erdenebileg;Chinbold, Enkhbold;Arques, Manel Sole;Donovan, Michael;Thung, Swan;Neely, Jaclyn;Mazzaferro, Vincenzo;Anderson, Jeffrey;Roayaie, Sasan;Schwartz, Myron;Villanueva, Augusto;Friedman, Scott L.;Uzilov, Andrew;Sia, Daniela;Llovet, Josep M.
我们之前报道了 HCC 免疫环境的特征，并描述了免疫特异性类别。我们现在的目标是进一步描述 HCC 的免疫基因组分类，以纳入解释免疫治疗反应/抵抗的特征。我们在一个由 240 名 HCC 患者组成的新队列中进行了 RNA 和全外显子组测序、TCR 测序、多重免疫荧光和免疫组织化学，并在由 660 名患者组成的其他队列中验证了我们的结果。我们的综合分析导致定义：a) 炎症型 HCC (37%)，其中包括先前报道的免疫亚类 (22%) 和新的免疫样亚类 (15%)，具有高干扰素信号传导、细胞溶解活性、免疫效应细胞因子的表达和更多样化的 T 细胞库。 20 个基因特征能够捕获约 90% 的肿瘤，并且与免疫治疗的反应相关。液体活检中鉴定的蛋白质概括了炎症类别，AUC 为 0.91； b) 中间类，富含 TP53 突变（49% vs 29%，p=0.035），以及涉及免疫相关基因的染色体丢失； c) 排除类，富含 CTNNB1 突变（93% vs 27%，p<0.001），并且由于基因扩增和启动子低甲基化而导致 PTK2 过度表达。排除类之外的 CTNNB1 突变导致 Wnt-β 连环蛋白通路激活较弱，或者发生在以高干扰素信号传导和 I 型抗原呈递基因为主的 HCC 中。我们已经描述了 HCC 的免疫基因组背景，并定义了炎症和非炎症肿瘤。描述了与免疫逃避中不同作用相关的两种不同的 CTNNB1 模式。这些特征可能有助于预测 HCC 的免疫反应。
We previously reported a characterization of the HCC immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. We performed RNA and whole-exome sequencing, TCR sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients. Our integrative analysis led to define: a) the Inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signaling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumors and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the Inflamed class with an AUC of 0.91; b) The Intermediate class, enriched in TP53 mutations (49 vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; c) the Excluded class, enriched in CTNNB1 mutations (93 vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the Excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signaling and type I antigen presenting genes. We have characterized the immunogenomic contexture of HCC and defined Inflamed and Non-inflamed tumors. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
15.9
作者：
Berglund, Anders;Mills, Matthew;Kim, Sungjune
通讯作者：
Kim, Sungjune
影响因子：
25.7
作者：
Cheng, Ann-Lii;Qin, Shukui;Finn, Richard S.
通讯作者：
Finn, Richard S.
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii