School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
Department of Pancreatic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Front Immunol. 2023 Mar 16;14:1076587. doi: 10.3389/fimmu.2023.1076587. eCollection 2023.
Metabolic reprogramming is a well-known hallmark of cancer. Systematical identification of clinically relevant metabolic subtypes of Hepatocellular carcinoma (HCC) is critical to understand tumor heterogeneity and develop efficient treatment strategies.
We performed an integrative analysis of genomic, transcriptomic, and clinical data from an HCC patient cohort in The Cancer Genome Atlas (TCGA).
Four metabolic subtypes were defined: mHCC1, mHHC2, mHCC3, and mHCC4. These subtypes had distinct differences in mutations profiles, activities of metabolic pathways, prognostic metabolism genes, and immune features. The mHCC1 was associated with poorest outcome and was characterized by extensive metabolic alterations, abundant immune infiltration, and increased expression of immunosuppressive checkpoints. The mHHC2 displayed lowest metabolic alteration level and was associated with most significant improvement in overall survival in response to high CD8+ T cell infiltration. The mHHC3 was a "cold-tumor" with low immune infiltration and few metabolic alterations. The mHCC4 presented a medium degree of metabolic alteration and high CTNNB1 mutation rate. Based on our HCC classification and in vitro study, we identified palmitoyl-protein thioesterase 1 (PPT1) was a specific prognostic gene and therapeutic target for mHCC1.
Our study highlighted mechanistic differences among metabolic subtypes and identified potential therapeutic targets for subtype-specific treatment strategies targeting unique metabolic vulnerabilities. The immune heterogeneities across metabolic subtypes may help further clarify the association between metabolism and immune environment and guide the development of novel strategies through targeting both unique metabolic vulnerabilities and immunosuppressive triggers.
代谢重编程是癌症的一个众所周知的标志。系统地识别肝癌（HCC）的临床相关代谢亚型对于理解肿瘤异质性和开发有效的治疗策略至关重要。
我们对癌症基因组图谱（TCGA）中 HCC 患者队列的基因组、转录组和临床数据进行了综合分析。
定义了四种代谢亚型：mHCC1、mHHC2、mHCC3 和 mHCC4。这些亚型在突变谱、代谢途径活性、预后代谢基因和免疫特征方面存在明显差异。mHCC1 与最差的预后相关，其特征是广泛的代谢改变、丰富的免疫浸润和免疫检查点的表达增加。mHHC2 显示出最低的代谢改变水平，与高 CD8+T 细胞浸润时总生存率的显著改善相关。mHHC3 是一种“冷肿瘤”，具有低免疫浸润和很少的代谢改变。mHCC4 表现出中等程度的代谢改变和高 CTNNB1 突变率。基于我们的 HCC 分类和体外研究，我们确定棕榈酰蛋白硫酯酶 1（PPT1）是 mHCC1 的一个特异性预后基因和治疗靶点。
我们的研究强调了代谢亚型之间的机制差异，并确定了针对独特代谢脆弱性的亚型特异性治疗策略的潜在治疗靶点。代谢亚型之间的免疫异质性可能有助于进一步阐明代谢与免疫环境之间的关联，并通过靶向独特的代谢脆弱性和免疫抑制触发因素指导新策略的制定。
