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.

中文翻译：

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人白细胞抗原DR15，可能是免疫检查点抑制剂引起的继发性肾上腺功能不全的可能预测指标。

背景技术尽管免疫检查点抑制剂（ICPis）在治疗各种晚期癌症方面具有有益作用，但它们仍会诱发各种免疫相关的不良事件（irAEs）。ICPi诱发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”。但是，其确切机制仍不清楚，也没有报道确定的预测标记。患者与方法我们招募并研究了11名患有垂体性irAEs的接受nivolumab，pembrolizumab或ipilimumab的晚期癌症患者（年龄在39-70岁； 6例男性患者）。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者的HLA等位基因频率。结果11例患者中，7例 3例和1例分别显示恶性黑色素瘤，非小细胞肺癌和胃癌。HLA类型筛查结果表明，分别在9、7和7例垂体irAE患者中观察到HLA-DR15，B52和Cw12。从日本HLA单倍型数据库（本研究与健康对照组）比较，我们组中DR15，B52和Cw12的患病率明显高于健康对照组。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irAE的诱发因素。据报道，HLA-DR15通过白介素17调节与自身免疫性疾病相关，表明其参与垂体irAE的发展。使用HLA单倍型作为垂体irAE的预测指标，