A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses

作者：Shaocong Mo, Bryan Jin, Yujen Tseng, Lingxi Lin, Lishuang Lin, Xin Shen, Huan Song, Mingjia Kong, Zhongguang Luo, Yiwei Chu, Chen Jiang, Zhiwei Cao, Jie Liu, Feifei Luo · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04326-w · 被引用次数：15 · 研究领域：Inflammatory Bowel Disease、Immune cells in cancer、Single-cell and spatial transcriptomics

BACKGROUND AND AIMS: We sought to identify novel molecular subtypes of ulcerative colitis (UC) based on large-scale cohorts and establish a clinically applicable subtyping system for the precision treatment of the disease. METHODS: Eight microarray profiles containing colon samples from 357 patients were utilized. Expression heterogeneity was screened out and stable subtypes were identified among UC patients. Immune infiltration pattern and biological agent response were compared among subtypes to assess the value in guiding treatment. The relationship between PRLR and TNFSF13B genes with the highest predictive value was further validated by functional experiments. RESULTS: Three stable molecular subtypes were successfully identified. Immune cell infiltration analysis defined three subtypes as innate immune activated UC (IIA), whole immune activated UC (WIA), and immune homeostasis like UC (IHL). Notably, the response rate towards biological agents (infliximab/vedolizumab) in WIA patients was the lowest (less than 10%), while the response rate in IHL patients was the highest, ranging from 42 to 60%. Among the featured genes of subtypes, the ratio of PRLR to TNFSF13B could effectively screen for IHL UC subtype suitable for biological agent therapies (Area under curve: 0.961-0.986). Furthermore, we demonstrated that PRLR expressed in epithelial cells could inhibit the expression of TNFSF13B in monocyte-derived macrophages through the CXCL1-NF-κB pathway. CONCLUSIONS: We identif...