A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses
Abstract 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 p...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Journal of Translational Medicine |
| Online Access: | https://doi.org/10.1186/s12967-023-04326-w |
| _version_ | 1797778701230800896 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shaocong Mo |
| collection | DOAJ |
| description | Abstract 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 identified three stable UC subtypes with a heterogeneous immune pattern and different response rates towards biological agents for the first time. We also established a precise molecular subtyping system and classifier to predict clinical drug response and provide individualized treatment strategies for UC patients. |
| first_indexed | 2024-03-12T23:21:18Z |
| format | Article |
| id | doaj.art-5fde9161b21141479943da05ca266e55 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-12T23:21:18Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-5fde9161b21141479943da05ca266e552023-07-16T11:26:32ZengBMCJournal of Translational Medicine1479-58762023-07-0121111810.1186/s12967-023-04326-wA precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responsesShaocong Mo0Bryan Jin1Yujen Tseng2Lingxi Lin3Lishuang Lin4Xin Shen5Huan Song6Mingjia Kong7Zhongguang Luo8Yiwei Chu9Chen Jiang10Zhiwei Cao11Jie Liu12Feifei Luo13Department of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityBiotherapy Research Center, Department of Immunology, School of Basic Medical Sciences and Institute of Biomedical Sciences, Fudan UniversityDepartment of Pharmaceutics, School of Pharmacy, Fudan UniversitySchool of Life Sciences, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityAbstract 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 identified three stable UC subtypes with a heterogeneous immune pattern and different response rates towards biological agents for the first time. We also established a precise molecular subtyping system and classifier to predict clinical drug response and provide individualized treatment strategies for UC patients.https://doi.org/10.1186/s12967-023-04326-w |
| spellingShingle | 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 A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses Journal of Translational Medicine |
| title | A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses |
| title_full | A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses |
| title_fullStr | A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses |
| title_full_unstemmed | A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses |
| title_short | A precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses |
| title_sort | precise molecular subtyping of ulcerative colitis reveals the immune heterogeneity and predicts clinical drug responses |
| url | https://doi.org/10.1186/s12967-023-04326-w |
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