Peng Li, Peng Jiang-Yun, Cai Dian-Kui, Qiu Yun-Tan, Lan Qiu-Sheng, Luo Jie, Yang Bing, Xie Hai-Tao, Du Ze-Peng, Yuan Xiao-Qing, Liu Yue, Yin Dong
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Oncol. 2022 Mar 3;12:780493. doi: 10.3389/fonc.2022.780493. eCollection 2022.
Super-enhancers (SEs) comprise large clusters of enhancers that highly enhance gene expression. Long non-coding RNAs (lncRNAs) tend to be dysregulated in cases of stomach adenocarcinoma (STAD) and are vital for balancing tumor immunity. However, whether SE-associated lncRNAs play a role in the immune infiltration of STAD remains unknown. In the present study, we identified SE-associated lncRNAs in the H3K27ac ChIP-seq datasets from 11 tumor tissues and two cell lines. We found that the significantly dysregulated SE-associated lncRNAs were strongly correlated with immune cell infiltration through the application of six algorithms (ImmuncellAI, CIBERSORT, EPIC, quantiSeq, TIMER, and xCELL), as well as immunomodulators and chemokines. We found that the expression of SE-associated lncRNA TM4SF1-AS1 was negatively correlated with the proportion of CD8+ T cells present in STAD. TM4SF1-AS1 suppresses T cell-mediated immune killing function and predicts immune response to anti-PD1 therapy. ChIP-seq, Hi-C and luciferase assay results verified that TM4SF1-AS1 was regulated by its super-enhancer. RNA-seq data showed that TM4SF1-AS1 is involved in immune and cancer-related processes or pathways. In conclusion, SE-associated lncRNAs are involved in the tumor immune microenvironment and act as indicators of clinical outcomes in STAD. This study highlights the importance of SE-associated lncRNAs in the immune regulation of STAD.
超级增强子（SEs）由大量高度增强基因表达的增强子簇组成。长链非编码RNA（lncRNAs）在胃腺癌（STAD）病例中往往失调，并且对平衡肿瘤免疫至关重要。然而，与SE相关的lncRNAs是否在STAD的免疫浸润中发挥作用仍不清楚。在本研究中，我们从11个肿瘤组织和两个细胞系的H3K27ac ChIP-seq数据集中鉴定出与SE相关的lncRNAs。通过应用六种算法（ImmuncellAI、CIBERSORT、EPIC、quantiSeq、TIMER和xCELL）以及免疫调节剂和趋化因子，我们发现显著失调的与SE相关的lncRNAs与免疫细胞浸润密切相关。我们发现与SE相关的lncRNA TM4SF1-AS1的表达与STAD中CD8+T细胞的比例呈负相关。TM4SF1-AS1抑制T细胞介导的免疫杀伤功能，并预测对抗PD1治疗的免疫反应。ChIP-seq、Hi-C和荧光素酶检测结果证实TM4SF1-AS1受其超级增强子调控。RNA-seq数据表明TM4SF1-AS1参与免疫和癌症相关的过程或途径。总之，与SE相关的lncRNAs参与肿瘤免疫微环境，并作为STAD临床结果的指标。本研究突出了与SE相关的lncRNAs在STAD免疫调节中的重要性。
