Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade
Abstract Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI the...
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2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54180-7 |
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| author | Chun-Bing Chen Shuen-Iu Hung John Wen-Cheng Chang Chan-Keng Yang David Hui-Kang Ma Yu-Chuan Teng Chun-Wei Lu Wei-Ti Chen Hsiao-Yin Yang Cheng-Chang Tsai Chih Liang Wang Pin-Hsuan Chiang Jennifer Wu Ya-Wen Tsai Lai-Ying Lu Yang Yu-Wei Lin Rosaline Chung-Yee Hui Fu-Mei Hsieh Chao-Kai Hsu Chaw-Ning Lee Yi-Ju Chen Chih-Chiang Chen Yilei Cui Hung-Chih Hsu Ya-Ching Chang Chih-Jung Chang Ho-Chen Lin Chee Jen Chang Yu-Jr Lin Cheng-Lung Ku Chuang-Wei Wang Wen-Hung Chung |
| author_facet | Chun-Bing Chen Shuen-Iu Hung John Wen-Cheng Chang Chan-Keng Yang David Hui-Kang Ma Yu-Chuan Teng Chun-Wei Lu Wei-Ti Chen Hsiao-Yin Yang Cheng-Chang Tsai Chih Liang Wang Pin-Hsuan Chiang Jennifer Wu Ya-Wen Tsai Lai-Ying Lu Yang Yu-Wei Lin Rosaline Chung-Yee Hui Fu-Mei Hsieh Chao-Kai Hsu Chaw-Ning Lee Yi-Ju Chen Chih-Chiang Chen Yilei Cui Hung-Chih Hsu Ya-Ching Chang Chih-Jung Chang Ho-Chen Lin Chee Jen Chang Yu-Jr Lin Cheng-Lung Ku Chuang-Wei Wang Wen-Hung Chung |
| author_sort | Chun-Bing Chen |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identify TNF signaling as a pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identify that macrophage-eliciting CTL contribute to the pathogenesis of ICI-induced epidermal necrolysis and provide potential therapeutic targets for the management and prevention of SCAR induced by ICI therapy. |
| format | Article |
| id | doaj-art-ff3e0e54616d424a89135bb548ffdd68 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ff3e0e54616d424a89135bb548ffdd682025-01-05T12:36:32ZengNature PortfolioNature Communications2041-17232024-12-0115111910.1038/s41467-024-54180-7Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockadeChun-Bing Chen0Shuen-Iu Hung1John Wen-Cheng Chang2Chan-Keng Yang3David Hui-Kang Ma4Yu-Chuan Teng5Chun-Wei Lu6Wei-Ti Chen7Hsiao-Yin Yang8Cheng-Chang Tsai9Chih Liang Wang10Pin-Hsuan Chiang11Jennifer Wu12Ya-Wen Tsai13Lai-Ying Lu14Yang Yu-Wei Lin15Rosaline Chung-Yee Hui16Fu-Mei Hsieh17Chao-Kai Hsu18Chaw-Ning Lee19Yi-Ju Chen20Chih-Chiang Chen21Yilei Cui22Hung-Chih Hsu23Ya-Ching Chang24Chih-Jung Chang25Ho-Chen Lin26Chee Jen Chang27Yu-Jr Lin28Cheng-Lung Ku29Chuang-Wei Wang30Wen-Hung Chung31Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchCancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou BranchCancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou BranchCollege of Medicine, Chang Gung UniversityCollege of Medicine, Chang Gung UniversityGenomic Medicine Core Laboratory, Chang Gung Memorial HospitalDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDepartment of Dermatology, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchBiotools Co. LtdDepartment of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityInstitute of Clinical Medicine, National Yang-Ming Chiao Tung UniversityInstitute of Clinical Medicine, National Yang-Ming Chiao Tung UniversityDepartment of Dermatology, University of Michigan Medical SchoolCancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDepartment of Dermatology, Xiamen Chang Gung HospitalDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchResearch Services Center for Health Information, Chang Gung UniversityResearch Services Center for Health Information, Chang Gung UniversityChang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchDrug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou BranchAbstract Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identify TNF signaling as a pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identify that macrophage-eliciting CTL contribute to the pathogenesis of ICI-induced epidermal necrolysis and provide potential therapeutic targets for the management and prevention of SCAR induced by ICI therapy.https://doi.org/10.1038/s41467-024-54180-7 |
| spellingShingle | Chun-Bing Chen Shuen-Iu Hung John Wen-Cheng Chang Chan-Keng Yang David Hui-Kang Ma Yu-Chuan Teng Chun-Wei Lu Wei-Ti Chen Hsiao-Yin Yang Cheng-Chang Tsai Chih Liang Wang Pin-Hsuan Chiang Jennifer Wu Ya-Wen Tsai Lai-Ying Lu Yang Yu-Wei Lin Rosaline Chung-Yee Hui Fu-Mei Hsieh Chao-Kai Hsu Chaw-Ning Lee Yi-Ju Chen Chih-Chiang Chen Yilei Cui Hung-Chih Hsu Ya-Ching Chang Chih-Jung Chang Ho-Chen Lin Chee Jen Chang Yu-Jr Lin Cheng-Lung Ku Chuang-Wei Wang Wen-Hung Chung Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade Nature Communications |
| title | Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade |
| title_full | Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade |
| title_fullStr | Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade |
| title_full_unstemmed | Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade |
| title_short | Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade |
| title_sort | immune checkpoint inhibitor induced severe epidermal necrolysis mediated by macrophage derived cxcl10 and abated by tnf blockade |
| url | https://doi.org/10.1038/s41467-024-54180-7 |
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