Department of Dermatology, University Hospital of Zürich, CH-8091, Zürich, Switzerland; Institute of Immunobiology, Kantonsspital St.Gallen, CH-9007, St. Gallen, Switzerland.
Institute of Immunobiology, Kantonsspital St.Gallen, CH-9007, St. Gallen, Switzerland.
Eur J Cancer. 2019 Jan;107:8-14. doi: 10.1016/j.ejca.2018.11.009. Epub 2018 Dec 7.
Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role.
We established a prospective observational single-centre study and collected data from patients with either metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma, who were treated with anti-PD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing.
We enrolled 102 patients (median [range] age, 68 [62-74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n = 32 (54%)) and rash (n = 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P > .05). When assessing each irAE individually, we found a significant association between HLA-DRB111:01 and pruritus (OR = 4.53, X = 9.45, P < .01) as well as a nominally significant additive association between HLA-DQB103:01 and colitis (OR = 3.94, X = 5.67, P = .017).
The presence of two HLA alleles that are known to predispose to autoimmune diseases were associated with the development of pruritus or colitis during therapy, suggesting a genetic aetiology of irAEs. Larger genome-wide association studies should be performed to confirm our findings.
检查点抑制剂（CIs）具有高度疗效，但可引起严重的免疫相关不良反应（irAEs），且无法预测。我们研究了人类白细胞抗原（HLA）基因是否易导致治疗期间发生 irAEs，从而具有预测作用。
我们建立了一项前瞻性观察性单中心研究，收集了接受抗 PD-1（程序性细胞死亡受体 1）、抗 CTLA4（细胞毒性 T 淋巴细胞相关蛋白 4）或两者联合 CIs 治疗的转移性非小细胞肺癌（NSCLC）或转移性黑色素瘤患者的数据。irAEs 数据包括 15 年 7 月 1 日至 18 年 5 月 10 日。此外，我们通过下一代测序进行 HLA 分型。
我们纳入了本研究中 102 名接受 CI 治疗的转移性癌症患者（中位[范围]年龄，68 [62-74] 岁）。其中，59 名（58%）患者发生了 1 种或多种 irAEs，其中瘙痒（n=32（54%））和皮疹（n=24（41%））发生率最高。我们未发现单个 HLA 基因与所有 irAEs 相关的证据（均 P>.05）。当评估每个 irAE 时，我们发现 HLA-DRB111:01 与瘙痒显著相关（OR=4.53，X=9.45，P<.01），HLA-DQB103:01 与结肠炎之间存在名义上的显著附加关联（OR=3.94，X=5.67，P=.017）。
两种已知易患自身免疫性疾病的 HLA 等位基因的存在与治疗期间瘙痒或结肠炎的发生相关，提示 irAEs 的遗传病因。应进行更大规模的全基因组关联研究来验证我们的发现。
