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Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency.

人白细胞抗原 DR15,免疫检查点抑制剂诱导的继发性肾上腺功能不全的可能预测标志物。

  • 影响因子:6.15
  • DOI:10.1016/j.ejca.2020.02.049
  • 作者列表:"Yano S","Ashida K","Sakamoto R","Sakaguchi C","Ogata M","Maruyama K","Sakamoto S","Ikeda M","Ohe K","Akasu S","Iwata S","Wada N","Matsuda Y","Nakanishi Y","Nomura M","Ogawa Y
  • 发表时间:2020-03-28
Abstract

BACKGROUND:Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS:We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS:Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS:HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.

摘要

背景: 免疫检查点抑制剂 (ICPis) 诱导各种免疫相关不良事件 (irAEs),尽管它们在治疗各种晚期癌症中的有益作用。ICPi 诱导的继发性肾上腺皮质功能不全被描述为一种普遍且严重的 “垂体 irAE”。然而,其确切机制仍不清楚,也没有明确的预测标志物的报道。 患者和方法: 我们招募并研究了 11 例接受 nivolumab 、 pembrolizumab 或 ipilimumab 治疗的晚期癌症患者 (年龄 39-70 岁; 6 例男性患者),这些患者发生了垂体白血病。回顾性评估其临床资料,包括内分泌功能,并测定人类白细胞抗原 (HLA) 基因型,比较这些患者和健康对照者的 HLA 等位基因频率。 结果: 11 例患者中,恶性黑色素瘤 7 例,非小细胞肺癌 3 例,胃癌 1 例。结果显示,垂体瘤患者分别有 9 例、 7 例和 7 例存在 HLA-DR15 、 B52 和 Cw12。DR15 、 B52 和 Cw12 在我们组中的患病率显著高于日本 HLA 单倍型数据库中的健康对照组 (本研究 vs 健康对照组); DR15: 81.8% vs 33.5% (n = 11,P = 0.0014),B52: 63.6% vs 21.0% (n = 11,P = 0.0026)和 Cw12: 70% vs 21.3% (n = 10,P = 0.0013)。 结论: HLA-DR15 、 B52 和 Cw12 可能是垂体瘤的易感因素。据报道,HLA-DR15 通过 interleukin-17 调节与自身免疫性疾病相关,提示其参与垂体 irAE 发育。利用 HLA 单倍型作为垂体 irAE 预测标志物,我们可以提供安全的 ICPi 治疗和了解 irAE 发病机制。

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