Dermatology Service, Division of Subspecialty Medicine, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pediatrics, National Jewish Health, Denver, Colorado.
Clin Cancer Res. 2024 Jul 1;30(13):2822-2834. doi: 10.1158/1078-0432.CCR-23-3431.
Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood.
Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays.
Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo.
Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.
免疫相关皮肤不良反应（ircAE）发生于≥50%接受检查点抑制剂治疗的患者中，但ircAE 的潜在机制尚不清楚。
对 200 例接受检查点抑制剂治疗的患者（139 例有 ircAE，61 例无（对照组））进行表型/生物标志物分析，以描述其临床表现和免疫内型。使用实时 PCR 和 Meso Scale Discovery 多重细胞因子分析，在皮肤活检、皮肤胶带提取物和血浆中评估细胞因子。
确定了 8 种 ircAE 表型：瘙痒（26%）、斑丘疹（MPR；21%）、湿疹（19%）、苔藓样（11%）、荨麻疹（8%）、银屑病样（6%）、白癜风（5%）和大疱性皮炎（4%）。所有表型均显示皮肤淋巴细胞和嗜酸性粒细胞浸润。皮肤活检 PCR 显示，苔藓样（P < 0.0001）和银屑病样皮炎（P < 0.01）患者的 IFNγ mRNA 增加最高，而湿疹患者的 IL13 mRNA 水平最高（P < 0.0001，与对照组相比）。IL17A mRNA 在银屑病样（P < 0.001）、苔藓样（P < 0.0001）、大疱性皮炎（P < 0.05）和 MPR（P < 0.001）中较对照组选择性增加。在皮肤胶带条和血浆中证实了不同的细胞因子谱。分析确定瘙痒时皮肤/血浆中 IL4 细胞因子增加，湿疹时皮肤中 IL13 增加，湿疹和荨麻疹时血浆中 IL5 和 IL31 增加，MPR 时混合细胞因子途径增加。皮质类固醇或 2 型细胞因子靶向抑制的广泛抑制导致这些 ircAE 的临床获益。相比之下，在银屑病样、苔藓样、大疱性皮炎和白癜风中发现 1 型/17 型途径的皮肤显著上调，以及白癜风中 1 型激活。
不同的免疫 ircAE 内型提示基于精准医学的干预具有可操作性的靶点。
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