A comprehensive metabonomic and transcriptomic analysis reveals how inhibiting glycolysis affects regulatory T cell proliferation

Blocking glycolysis inhibits regulatory T cells (Tregs), which are often hijacked by tumor cells whose survival relies on glycolysis to inhibit antitumor immunity. However, how glycolysis influences Treg proliferation/differentiation remains unclear. Monocarboxylate transporters (MCTs) are key regulatory proteins that affect glycolysis. To describe the potential mechanism underlying the effect of glycolysis on Treg proliferation and differentiation as well as the role of MCT1 on Treg metabolism, we conducted a comprehensive metabonomic and transcriptomic analysis using omics and molecular biology techniques. Fifteen differential metabolites and 2232 differentially expressed genes (DEGs) were identified, which were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to determine the most widely affected pathways. The results revealed that the adenosine triphosphate-binding cassette (ABC) transporter metabolism pathway was the most differentially activated between these two groups. According to The Cancer Genome Atlas (TCGA) database, the expression of ABC transporter-related genes affects renal clear cell carcinoma prognosis and is closely related to tumor immune cell infiltration. The comprehensive analysis showed that MCT1-induced ABC transporter disorder has important effects on Treg biology. These insights will help to clarify the mechanism of MCT1-induced Treg growth inhibition and emphasize the importance of omics research for deepening the understanding of tumor cell proliferation mechanisms.

阻断糖酵解可抑制调节性T细胞（regulatory T cells, Tregs），而肿瘤细胞常劫持此类细胞，且其存活依赖糖酵解以抑制抗肿瘤免疫。然而，糖酵解如何影响调节性T细胞的增殖与分化，目前仍不明确。单羧酸转运蛋白（monocarboxylate transporters, MCTs）是调控糖酵解的关键蛋白。为阐明糖酵解调控调节性T细胞增殖与分化的潜在机制，以及单羧酸转运蛋白1（MCT1）在调节性T细胞代谢中的作用，本研究采用组学与分子生物学技术，开展了全面的代谢组学与转录组学分析。本研究共鉴定出15种差异代谢物与2232个差异表达基因（differentially expressed genes, DEGs），随后对其开展京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析，以筛选出受影响最显著的通路。结果显示，腺苷三磷酸结合盒（adenosine triphosphate-binding cassette, ABC）转运体代谢通路是两组间差异激活程度最高的通路。基于癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库的分析表明，ABC转运体相关基因的表达可影响肾透明细胞癌的预后，且与肿瘤免疫细胞浸润密切相关。综合分析显示，MCT1介导的ABC转运体功能紊乱对调节性T细胞的生物学功能具有重要调控作用。本研究所得结论有助于阐明MCT1介导的调节性T细胞增殖抑制机制，同时凸显了组学研究对于深化肿瘤细胞增殖机制认知的重要价值。