Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Rd, Wuhan, China.
J Transl Med. 2023 Feb 24;21(1):146. doi: 10.1186/s12967-023-03978-y.
Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative.
Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity.
Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8 T cells.
Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations.
肾癌经历了显著的代谢转变，并已表现出对免疫治疗干预的反应。然而，代谢分类以及代谢改变与肾细胞癌免疫浸润之间的关联仍有待阐明。
对 TCGA 队列进行无监督共识聚类，进行代谢分类。比较 GESA、mRNAsi、预后、临床特征、突变负荷、免疫浸润和不同簇之间差异表达基因的差异。基于代谢基因特征构建预后模型和列线图，并使用外部 ICGC 数据集进行验证。使用 Human Protein Atlas 数据库和同济医院的免疫组织化学结果验证正常组织和肿瘤样本中的基因表达水平。应用 CCK8、凋亡分析、qPCR、皮下植入小鼠模型和流式细胞术分析来研究 ACAA2 在肿瘤进展和抗肿瘤免疫中的作用。
将肾细胞癌分为 3 个代谢亚群，代谢谱低的亚群预后最差，侵袭性和 AJCC 分级最高，免疫浸润增强，但免疫表型抑制。鉴定出 ACAA2、ACAT1、ASRGL1、AKR1B10、ABCC2、ANGPTL4 来构建 6 基因特征预后模型，并通过 ICGC 队列进行内部和外部验证。ACAA2 被证明是一种肿瘤抑制因子，与更高的免疫浸润和 CD8 T 细胞 PD-1 表达升高有关。
本研究提出了一种新的 RCC 代谢分类方法，并揭示了代谢表型与免疫表型之间的内在关联。鉴定的基因特征可能是连接肿瘤代谢和肿瘤免疫的关键因素，值得进一步深入研究。
