Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, China.
EBioMedicine. 2019 Apr;42:363-374. doi: 10.1016/j.ebiom.2019.03.022. Epub 2019 Mar 16.
BACKGROUND: TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC. METHODS: We investigated TP53 mutation status and RNA expression in different populations and platforms and developed an immune prognostic model (IPM) based on immune-related genes that were differentially expressed between TP53 and TP53 HCC samples. Then, the influence of the IPM on the immune microenvironment in HCC was comprehensively analysed. FINDINGS: TP53 mutation resulted in the downregulation of the immune response in HCC. Thirty-seven of the 312 immune response-related genes were differentially expressed based on TP53 mutation status. An IPM was established and validated based on 865 patients with HCC to differentiate patients with a low or high risk of poor survival. A nomogram was also established for clinical application. Functional enrichment analysis showed that the humoral immune response and immune system diseases pathway represented the major function and pathway, respectively, related to the IPM genes. Moreover, we found that the patients in the high-risk group had higher fractions of T cells follicular helper, T cells regulatory (Tregs) and macrophages M0 and presented higher expression of CTLA-4, PD-1 and TIM-3 than the low-risk group. INTERPRETATION: TP53 mutation is strongly related to the immune microenvironment in HCC. Our IPM, which is sensitive to TP53 mutation status, may have important implications for identifying subgroups of HCC patients with low or high risk of unfavourable survival. FUND: This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten Thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), and the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001).
背景：TP53 突变是肝细胞癌（HCC）中最常见的突变，它影响 HCC 的进展和预后。我们研究了 TP53 突变如何调节 HCC 的免疫表型，从而影响 HCC 的预后。
方法：我们研究了不同人群和平台中 TP53 突变状态和 RNA 表达，并基于 TP53 和 TP53 HCC 样本之间差异表达的免疫相关基因开发了一种免疫预后模型（IPM）。然后，全面分析了 IPM 对 HCC 免疫微环境的影响。
发现：TP53 突变导致 HCC 中免疫反应下调。根据 TP53 突变状态，312 个免疫反应相关基因中有 37 个基因表达差异。基于 865 例 HCC 患者建立并验证了 IPM，以区分低或高生存不良风险的患者。还建立了用于临床应用的列线图。功能富集分析表明，体液免疫反应和免疫系统疾病途径分别代表与 IPM 基因相关的主要功能和途径。此外，我们发现高危组患者滤泡辅助性 T 细胞、调节性 T 细胞（Tregs）和 M0 巨噬细胞的比例更高，并且 CTLA-4、PD-1 和 TIM-3 的表达更高。
结论：TP53 突变与 HCC 的免疫微环境密切相关。我们的 IPM 对 TP53 突变状态敏感，可能对识别 HCC 患者中低或高不良生存风险亚组具有重要意义。
资助：本工作得到国际科技合作项目（2016YFE0107100）、首都卫生发展科研专项基金（2014-2-4012）、北京市自然科学基金（L172055 和 7192158）、国家万人计划、中央高校基本科研业务费专项资金（3332018032）和中国医学科学院医学与健康科技创新工程（CIFMS）（2017-I2M-4-003 和 2018-I2M-3-001）的支持。
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