Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
Eur J Cancer. 2020 May;130:198-203. doi: 10.1016/j.ejca.2020.02.049. Epub 2020 Mar 28.
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.
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.
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).
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.
免疫检查点抑制剂（ICPis）在治疗各种晚期癌症方面具有有益作用，但会引发各种免疫相关不良事件（irAEs）。ICP 诱导的继发性肾上腺功能不全被描述为一种常见且严重的“垂体 irAE”。然而，其确切的机制尚不清楚，也没有报道明确的预测标志物。
我们招募并研究了 11 名患有晚期癌症（年龄 39-70 岁；男性 6 名）的患者，他们接受了纳武单抗、帕博利珠单抗或伊匹单抗治疗，发生了垂体 irAE。回顾性评估了他们的临床数据，包括内分泌功能，并确定了人类白细胞抗原（HLA）基因型，以比较这些患者和健康对照组的 HLA 等位基因频率。
在 11 名患者中，7 名、3 名和 1 名患者分别患有恶性黑色素瘤、非小细胞肺癌和胃癌。HLA 类型筛选结果显示，9 例、7 例和 7 例垂体 irAE 患者分别出现 HLA-DR15、B52 和 Cw12。与日本 HLA 单倍型数据库中的健康对照组相比，我们组中 DR15、B52 和 Cw12 更为常见（本研究与健康对照组相比）；DR15：81.8%比 33.5%（n=11，P=0.0014），B52：63.6%比 21.0%（n=11，P=0.0026）和 Cw12：70%比 21.3%（n=10，P=0.0013）。
HLA-DR15、B52 和 Cw12 可能是垂体 irAE 的易感因素。据报道，HLA-DR15 通过调节白细胞介素-17 与自身免疫性疾病有关，提示其参与垂体 irAE 的发生发展。使用 HLA 单倍型作为垂体 irAE 的预测标志物，我们可以提供安全的 ICPi 治疗，并了解 irAE 的发病机制。
