Immune Infiltration and Clinical Outcome of Super-Enhancer-Associated lncRNAs in Stomach Adenocarcinoma

Li Peng; Jiang-Yun Peng; Dian-Kui Cai; Yun-Tan Qiu; Qiu-Sheng Lan; Jie Luo; Bing Yang; Hai-Tao Xie; Ze-Peng Du; Xiao-Qing Yuan; Yue Liu; Dong Yin

doi:10.3389/fonc.2022.780493

Immune Infiltration and Clinical Outcome of Super-Enhancer-Associated lncRNAs in Stomach Adenocarcinoma

Front Oncol. 2022 Mar 3:12:780493. doi: 10.3389/fonc.2022.780493. eCollection 2022.

Authors

Li Peng^{1

2}, Jiang-Yun Peng^{1

2}, Dian-Kui Cai^{1

3}, Yun-Tan Qiu^{1

2}, Qiu-Sheng Lan^{1

4}, Jie Luo^{1

5}, Bing Yang^{1

2}, Hai-Tao Xie⁵, Ze-Peng Du⁶, Xiao-Qing Yuan^{1

7}, Yue Liu⁸, Dong Yin^{1

2}

Affiliations

¹ 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.
² Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
³ Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁴ Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁵ Department of Clinical Laboratory, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
⁶ Central Laboratory, Department of Pathology, Shantou Central Hospital, Shantou, China.
⁷ Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁸ Institute of Digestive Disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.

Abstract

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.

Keywords: PD1; T cell; TM4SF1-AS1; clinical outcome; immune infiltration; long non-coding RNA (IncRNA); stomach adenocarcinoma (STAD); super-enhancer (SE).