肿瘤免疫微环境特征分析鉴定出 M0 巨噬细胞富集簇是肝细胞癌的一个不良预后因素。
Characterization of the Tumor Immune Microenvironment Identifies M0 Macrophage-Enriched Cluster as a Poor Prognostic Factor in Hepatocellular Carcinoma.
机构信息
Department of Medical Education, University of Michigan Medical School, Ann Arbor, MI.
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
出版信息
JCO Clin Cancer Inform. 2020 Oct;4:1002-1013. doi: 10.1200/CCI.20.00077.
PURPOSE
Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and a high recurrence rate. The tumor immune microenvironment in HCC has been characterized as shifted toward immunosuppression. We conducted a genomic data-driven classification of immune microenvironment HCC subtypes. In addition, we demonstrated their prognostic value and suggested a potential therapeutic targeting strategy.
METHODS
RNA sequencing data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma was used (n = 366). Abundance of immune cells was imputed using CIBERSORT and visualized using unsupervised hierarchic clustering. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox regression. Differential expression and gene set enrichment analyses were conducted on immune clusters with poor OS and high programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) coexpression. A scoring metric combining differentially expressed genes and immune cell content was created, and its prognostic value and immune checkpoint blockade response prediction was evaluated.
RESULTS
Two clusters were characterized by macrophage enrichment, with distinct M0 and M2 subtypes. M2 ( = .038) and M0 ( = .018) were independently prognostic for OS on multivariable analysis. Kaplan-Meier estimates demonstrated that patients in M0 and M2 treated with sorafenib had decreased OS ( = .041), and angiogenesis hallmark genes were enriched in the M0 group. CXCL6 and POSTN were overexpressed in both the M0 and the PD-1/PD-L1 groups. A score consisting of and expression and absolute M0 macrophage content was discriminatory for OS (intermediate: hazard ratio [HR], 1.59; ≤ .001; unfavorable: HR, 2.08; = .04).
CONCLUSION
Distinct immune cell clusters with macrophage predominance characterize an aggressive HCC phenotype, defined molecularly by angiogenic gene enrichment and clinically by poor prognosis and sorafenib response. This novel immunogenomic signature may aid in stratification of unresectable patients to receive checkpoint inhibitor and antiangiogenic therapy combinations.
目的
肝细胞癌（HCC）的预后较差，复发率较高。HCC 的肿瘤免疫微环境已被确定为向免疫抑制倾斜。我们进行了基于基因组数据的 HCC 免疫微环境亚型分类。此外，我们还展示了它们的预后价值，并提出了一种潜在的治疗靶向策略。
方法
使用来自癌症基因组图谱-肝肝细胞癌的 RNA 测序数据（n = 366）。使用 CIBERSORT 对免疫细胞的丰度进行估算，并使用无监督层次聚类进行可视化。使用 Kaplan-Meier 估计和 Cox 回归分析总生存期（OS）。对 OS 较差且程序性死亡-1（PD-1）/程序性死亡配体 1（PD-L1）共表达较高的免疫簇进行差异表达和基因集富集分析。创建了一个组合差异表达基因和免疫细胞含量的评分指标，并评估了其预后价值和免疫检查点阻断反应预测。
结果
两个簇的特征是巨噬细胞丰富，具有明显的 M0 和 M2 亚型。M2（ =.038）和 M0（ =.018）在多变量分析中独立预测 OS。Kaplan-Meier 估计表明，M0 和 M2 组接受索拉非尼治疗的患者 OS 降低（ =.041），并且 M0 组中富含血管生成特征基因。CXCL6 和 POSTN 在 M0 组和 PD-1/PD-L1 组中均过表达。由 和 表达和绝对 M0 巨噬细胞含量组成的评分指标对 OS 具有鉴别力（中值：危险比 [HR]，1.59； ≤.001；不利：HR，2.08； =.04）。
结论
具有巨噬细胞优势的不同免疫细胞簇特征是一种侵袭性 HCC 表型，其分子特征为血管生成基因富集，临床特征为预后不良和索拉非尼反应。这种新的免疫基因组特征可能有助于对不可切除患者进行分层，以接受检查点抑制剂和抗血管生成治疗联合治疗。
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