ICI-SJS/TEN 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 examined 6 cohorts within 25 ICI-induced SJS/TEN patients and conducted single-cell RNA sequencing (scRNA-seq) analysis, which revealed overexpression of macrophage-derived CXCL10 that recruited CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identified TNF signaling as the key 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 identified that macrophage-eliciting CTL contribute the pathogenesis of ICI-induced epidermal necrolysis and provide the therapeutic targets for the management and prevention of SCAR induced by ICI therapy. Overall design: Single-cell RNA Sequencing

免疫检查点抑制剂（Immune Checkpoint Inhibitors, ICI）是一类新型抗肿瘤药物，目前已在全球范围内得到广泛应用。然而，ICI可能诱发危及生命的重症皮肤不良反应（severe cutaneous adverse reaction, SCAR），例如史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症（Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, SJS/TEN），进而阻碍ICI的持续治疗。本研究纳入25例ICI诱导的SJS/TEN患者中的6个队列，开展单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）分析，结果显示，在ICI-SJS/TEN皮损的水疱细胞中，巨噬细胞来源的CXCL10呈高表达，可招募CXCR3+细胞毒性T淋巴细胞（cytotoxic T lymphocytes, CTL）。单细胞RNA表达谱分析与体外阻断实验进一步证实，肿瘤坏死因子（Tumor Necrosis Factor, TNF）信号通路是调控巨噬细胞来源CXCL10表达及CTL活化的关键通路。基于轨迹分析，本研究推测外周血中经ICI活化的T细胞是炎症启动的初始细胞，可促使单核细胞分化为巨噬细胞，并增强巨噬细胞向皮损部位迁移的易感性。与全身性糖皮质激素治疗相比，接受生物制剂靶向TNF阻断治疗的ICI诱导SJS/TEN患者，其恢复速度显著更快，且在持续ICI治疗过程中未出现SCAR复发。本研究结果证实，巨噬细胞介导的CTL活化参与了ICI诱导的表皮坏死松解症的发病机制，并为ICI治疗相关SCAR的管理与预防提供了治疗靶点。研究设计：单细胞RNA测序