Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade

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<sup>+</sup> 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.

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Publication Details

Journal
Nature Communications
Published
2024-12-30
DOI
https://doi.org/10.1038/s41467-024-54180-7
Citations
19
Primary Topic
Drug-Induced Adverse Reactions
Type
article
Field-Weighted Citation Impact
8.51

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article

Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade

Fu-Mei Hsieh, Pin‐Hsuan Chiang, Chuang‐Wei Wang, Rosaline Chung‐Yee Hui et al.
19 citations
Nature Communications
Drug-Induced Adverse Reactions
8.51
article

Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade

Fu-Mei Hsieh, Pin‐Hsuan Chiang, Chuang‐Wei Wang, Rosaline Chung‐Yee Hui, Chaw‐Ning Lee, Chun‐Wei Lu, Hsiao-Yin Yang, Hung‐Chih Hsu, Chao‐Kai Hsu, Lai‐Ying Lu, Wen‐Hung Chung, Ya‐Wen Tsai, Ho-Chen Lin, Chun‐Bing Chen, Chih‐Jung Chang, Chee‐Jen Chang, Ya-Ching Chang, Cheng‐Lung Ku, Chih Liang Wang, Lin Yang, Cheng‐Chang Tsai, John Wen-Cheng Chang, Yu‐Jr Lin, Yilei Cui, Wen‐Hung Chung, Chih‐Chiang Chen, Jennifer D. Wu, Yi‐Yu Chen, David Hui‐Kang, Yu-Chuan Teng, Chan‐Keng Yang, Wei‐Ti Chen
article en
19 citations

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<sup>+</sup> 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.

Nature CommunicationsVol. 15(1)
Huaqiao University (CN), Chang Gung University of Science and Technology (TW), National Yang Ming Chiao Tung University (TW), Chang Gung University (TW), National Tsing Hua University (TW), University of Michigan (US), Ruijin Hospital (CN), Taipei Veterans General Hospital (TW), Chang Gung Memorial Hospital (TW), Taichung Veterans General Hospital (TW), Keelung Chang Gung Memorial Hospital (TW), Linkou Chang Gung Memorial Hospital (TW), Taipei City Hospital (TW), Xiamen Chang Gung Hospital (CN), Beijing Tsinghua Chang Gung Hospital (CN), National Cheng Kung University Hospital (TW)
Chang Gung Memorial Hospital, Chang Gung Medical Foundation, Chang Gung Memorial Hospital, Linkou, National Science and Technology Council
Good health and well-being
Openalex Percentile: Top 2%
Drug-Induced Adverse Reactions
8.51
DOIOpen Access PDFOpenAlex
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