HES6 Mediates Oxidative Phosphorylation Pathway to Promote Immune Infiltration of CD8 + T Cells in Lung Adenocarcinoma.

IF 3.2 4区 医学 Q3 IMMUNOLOGY
Journal of Immunotherapy Pub Date : 2024-10-01 Epub Date: 2024-07-15 DOI:10.1097/CJI.0000000000000535
Zhoumiao Chen, Yongliang Wang, Weijian Tang, Shaohua Xu, Hao Yu, Zhao Chen
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引用次数: 0

Abstract

Tumor immunotherapy has recently gained popularity as a cancer treatment strategy. The molecular mechanism controlling immune infiltration in lung adenocarcinoma (LUAD) cells, however, is not well characterized. Investigating the immune infiltration modulation mechanism in LUAD is crucial. LUAD patient samples were collected, and HES6 expression and immune infiltration level of CD8 + T cells in patient tissues were analyzed. Bioinformatics was utilized to identify binding relationship between E2F1 and HES6, and enrichment pathway of HES6. The binding of E2F1 to HES6 was verified using dual-luciferase and ChIP experiments. HES6 and E2F1 expression in LUAD cells was detected. LUAD cells were co-cultured with CD8 + T cells, and the CD8 + T cell killing level, IFN-γ secretion, and CD8 + T-cell chemotaxis level were measured. Expression of key genes involved in oxidative phosphorylation was detected, and the oxygen consumption rate of LUAD cells was assessed. A mouse model was constructed to assay Ki67 expression and apoptosis in tumor tissue. High expression of HES6 promoted CD8 + T-cell infiltration and enhanced T-cell killing ability through oxidative phosphorylation. Further bioinformatics analysis, molecular experiments, and cell experiments verified that E2F1 negatively regulated HES6 by oxidative phosphorylation, which suppressed CD8 + T-cell immune infiltration. In addition, in vivo assays illustrated that silencing HES6 repressed tumor cell immune evasion. E2F1 inhibited HES6 transcription, thereby mediating oxidative phosphorylation to suppress immune infiltration of CD8 + T cells in LUAD. The biological functions and signaling pathways of these genes were analyzed, which may help to understand the possible mechanisms regulating immune infiltration in LUAD.

HES6介导氧化磷酸化通路,促进CD8+T细胞对肺腺癌的免疫渗透
作为一种癌症治疗策略,肿瘤免疫疗法近来越来越受欢迎。然而,控制肺腺癌(LUAD)细胞免疫浸润的分子机制尚不十分明确。研究 LUAD 的免疫浸润调节机制至关重要。研究人员收集了 LUAD 患者样本,分析了患者组织中 HES6 的表达和 CD8+ T 细胞的免疫浸润水平。利用生物信息学方法确定了E2F1与HES6的结合关系以及HES6的富集途径。利用双荧光素酶和ChIP实验验证了E2F1与HES6的结合。检测 LUAD 细胞中 HES6 和 E2F1 的表达。将 LUAD 细胞与 CD8+ T 细胞共培养,测定 CD8+ T 细胞杀伤水平、IFN-γ 分泌和 CD8+ T 细胞趋化水平。检测了参与氧化磷酸化的关键基因的表达,并评估了LUAD细胞的耗氧率。建立了一个小鼠模型来检测肿瘤组织中 Ki67 的表达和凋亡。HES6的高表达促进了CD8+ T细胞的浸润,并通过氧化磷酸化增强了T细胞的杀伤能力。进一步的生物信息学分析、分子实验和细胞实验证实,E2F1通过氧化磷酸化负调控HES6,从而抑制了CD8+ T细胞的免疫浸润。此外,体内实验表明,沉默 HES6 可抑制肿瘤细胞的免疫逃避。E2F1抑制了HES6的转录,从而介导氧化磷酸化抑制了LUAD中CD8+ T细胞的免疫浸润。分析了这些基因的生物学功能和信号通路,有助于了解调控LUAD免疫浸润的可能机制。
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来源期刊
Journal of Immunotherapy
Journal of Immunotherapy 医学-免疫学
CiteScore
6.90
自引率
0.00%
发文量
79
审稿时长
6-12 weeks
期刊介绍: Journal of Immunotherapy features rapid publication of articles on immunomodulators, lymphokines, antibodies, cells, and cell products in cancer biology and therapy. Laboratory and preclinical studies, as well as investigative clinical reports, are presented. The journal emphasizes basic mechanisms and methods for the rapid transfer of technology from the laboratory to the clinic. JIT contains full-length articles, review articles, and short communications.
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