The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.
Department of Dermatology, Wakayama Medical University, Wakayama, Japan.
Cancer Sci. 2020 May;111(5):1468-1477. doi: 10.1111/cas.14363. Epub 2020 Mar 17.
Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1β, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
免疫相关不良事件（irAEs）在各种恶性肿瘤的免疫检查点抑制剂（ICI）治疗中经常发生。内分泌 irAEs 包括甲状腺功能障碍是最常见的 irAEs，但它们的生物标志物仍不清楚。为了确定易发生甲状腺 irAE 的个体，以便早期诊断和适当随访，本研究旨在探讨甲状腺 irAE 的生物标志物。在此，前瞻性研究了接受 ICI 治疗的晚期恶性疾病患者。在基线时和首次接受 ICI 治疗后每 4 周评估临床和实验室检查、甲状腺功能和自身抗体。在基线和 4 周时测量细胞因子/趋化因子。评估 ICI 对实验性自身免疫性甲状腺炎的体内作用。本研究纳入了 26 名接受 ICI 治疗的恶性疾病患者。患者分为两组：发生甲状腺 irAE 组和无 irAE 组。比较两组患者，甲状腺 irAE 组在基线时和 4 周时出现血清甲状腺球蛋白（Tg）水平和甲状腺自身抗体的早期升高（≤4 周）（P <.05）。值得注意的是，基线时血清 IL-1β、IL-2 和 GM-CSF 水平较高，IL-8、G-CSF 和 MCP-1 早期下降与甲状腺 irAE 的发生显著相关（P <.05）。抗 PD-1 抗体对小鼠实验性甲状腺炎恶化的体内作用。总之，Tg、甲状腺自身免疫和细胞因子水平的早期变化可能预示着甲状腺 irAE 的发生。预先存在的甲状腺自身免疫可能与甲状腺 irAE 的发生有关。这些因素作为肿瘤治疗替代生物标志物的潜在应用得到了提示。
