Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Transl Med. 2013 Aug 21;5(199):199ra110. doi: 10.1126/scitranslmed.3005773.
Cancer patients treated with anti-EGFR (epidermal growth factor receptor) drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients' plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Before lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells, and neutrophils. As the skin phenotype evolved, changes in blood counts and circulating chemokines reproduced those seen in the gefitinib-treated patients. Crossing the mutant mice with mice deficient for tumor necrosis factor-α (TNF-α) receptors, MyD88, NOS2, CCR2, T cells, or B cells failed to reverse the skin phenotype. However, local depletion of macrophages provided partial resolution, suggesting that this model can identify targets that may be effective in preventing the troublesome and dose-limiting skin response to anti-EGFR drugs. These results highlight the importance of EGFR signaling in maintaining skin immune homeostasis and identify a macrophage contribution to a serious adverse consequence of cancer chemotherapy.
接受抗 EGFR（表皮生长因子受体）药物治疗的癌症患者常出现一种病因不明的剂量限制瘙痒性皮疹。我们的研究目的是从接受吉非替尼治疗的患者的皮肤和全身变化的临床研究中确定因果关联，并利用这些关联开发和表征一种可重现抗 EGFR 治疗引起的人类皮疹综合征的小鼠模型。我们在接受吉非替尼治疗前后检查了患者的血浆，并记录了与皮疹程度或瘙痒存在相关的趋化因子和白细胞计数的变化。我们通过在表皮中敲除 EGFR 建立了一个平行的小鼠模型。这些小鼠出现了类似于人类皮疹的皮肤损伤。在病变发展之前，我们检测到与早期浸润的巨噬细胞和肥大细胞以及随后浸润的嗜酸性粒细胞、T 细胞和中性粒细胞相关的皮肤中趋化因子的 mRNA 表达增加。随着皮肤表型的演变，血液计数和循环趋化因子的变化复制了接受吉非替尼治疗的患者的变化。将突变小鼠与缺乏肿瘤坏死因子-α（TNF-α）受体、MyD88、NOS2、CCR2、T 细胞或 B 细胞的小鼠杂交未能逆转皮肤表型。然而，巨噬细胞的局部耗竭提供了部分缓解，表明该模型可确定可能有效预防抗 EGFR 药物引起的麻烦和剂量限制皮肤反应的靶点。这些结果强调了 EGFR 信号在维持皮肤免疫稳态中的重要性，并确定了巨噬细胞对癌症化疗严重不良后果的贡献。
