PDF(Pubmed)
Abstract：
Rationale: CD8+ T cells undergo a series of metabolic reprogramming processes during their activation and proliferation, including increased glycolysis, decreased aerobic oxidation of sugars, increased amino acid metabolism and increased protein synthesis. However, it is still unclear what factors regulate these metabolic reprogramming processes in CD8+ T cells in the tumor immune microenvironment. Methods: T cell chromobox protein 4 (CBX4) knock-out mice models were used to determine the role of CBX4 in CD8+ T cells on the tumor immune microenvironment and tumor progression. Flow cytometry, Cut-Tag qPCR, Chip-seq, immunoprecipitation, metabolite detection, lentivirus infection and adoptive T cells transfer were performed to explore the underlying mechanisms of CBX4 knock-out in promoting CD8+ T cell activation and inhibiting tumor growth. Results: We found that CBX4 expression was induced in tumor-infiltrating CD8+ T cells and inhibited CD8+ T cell function by regulating glucose metabolism in tumor tissue. Mechanistically, CBX4 increases the expression of the metabolism-associated molecule aldolase B (Aldob) through sumoylation of trans-acting transcription factor 1 (SP1) and Krüppel-like factor 3 (KLF3). In addition, Aldob inhibits glycolysis and ATP synthesis in T cells by reducing the phosphorylation of the serine/threonine protein kinase (Akt) and ultimately suppresses CD8+ T cell function. Significantly, knocking out CBX4 may improve the efficacy of anti-PD-1 therapy by enhancing the function of CD8+ T cells in the tumor microenvironment. Conclusion: CBX4 is involved in CD8+ T cell metabolic reprogramming and functional persistence in tumor tissues, and serves as an inhibitor in CD8+ T cells\' glycolysis and effector function.
摘要：
原理：CD8+T细胞在其激活和增殖过程中经历一系列代谢重编程过程，包括糖酵解增加，减少糖的有氧氧化，氨基酸代谢增加，蛋白质合成增加。然而,目前尚不清楚是什么因素在肿瘤免疫微环境中调节CD8+T细胞的这些代谢重编程过程.方法:采用T细胞染色盒蛋白4(CBX4)敲除小鼠模型,确定CD8+T细胞中CBX4对肿瘤免疫微环境和肿瘤进展的作用。流式细胞术,Cut-TagqPCR,Chip-seq,免疫沉淀,代谢物检测，进行慢病毒感染和过继性T细胞转移，以探讨CBX4敲除促进CD8T细胞活化和抑制肿瘤生长的潜在机制。结果：我们发现CBX4在肿瘤浸润的CD8T细胞中被诱导表达，并通过调节肿瘤组织中的糖代谢来抑制CD8T细胞的功能。机械上,CBX4通过反式作用转录因子1（SP1）和Krüppel样因子3（KLF3）的sumoylation增加代谢相关分子醛缩酶B（Aldob）的表达。此外,Aldob通过减少丝氨酸/苏氨酸蛋白激酶（Akt）的磷酸化来抑制T细胞中的糖酵解和ATP合成，并最终抑制CD8T细胞功能。重要的是,敲除CBX4可能通过增强肿瘤微环境中CD8+T细胞的功能来提高抗PD-1治疗的疗效。结论:CBX4参与肿瘤组织中CD8+T细胞代谢重编程和功能持久性,并作为CD8+T细胞糖酵解和效应子功能的抑制剂。
