Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors
Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors
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DOI：
10.1016/j.ejca.2018.11.009
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发表时间：
2019-01-01
影响因子：
8.4
通讯作者：
Flatz, Lukas
中科院分区：
文献类型：
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作者：
Ali, Omar Hasan;Berner, Fiamma;Flatz, Lukas
背景：检查点抑制剂（CI）非常有效，但可诱导严重的免疫相关不良事件（irAE），这是无法预测的。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irAE，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，并收集了接受抗PD-1治疗的转移性非小细胞肺癌（NSCLC）或转移性黑素瘤患者的数据（程序性细胞死亡受体1）、抗CTLA 4（细胞毒性T淋巴细胞相关蛋白4）或两种CI组合。数据包括irAE，范围为2016年7月15日至2018年5月10日。此外，我们通过下一代测序进行HLA分型。结果：我们纳入了102例接受CI治疗的转移性癌症患者（中位[范围]年龄为68 [62-74]岁）。在这些患者中，59例（58%）发生了1起或多起irAE，其中瘙痒（n = 32（54%））和皮疹（n = 24（41%））的发生率最高。我们没有发现单个HLA基因与所有irAE相关的证据（所有P > 0.05）。当单独评估每种irAE时，我们发现HLA-DRB 1 *11：01与瘙痒症之间存在显著相关性（OR = 4.53，X-1，95（2）= 9.45，P <0.01）以及HLA-DQB 1 *03：01与结肠炎之间名义上显著的相加关联（OR = 3.94，X-1，95（2）= 5.67，P = .017）。已知易患自身免疫性疾病的两个HLA等位基因的存在与治疗期间瘙痒或结肠炎的发生相关，表明irAE的遗传病因学。应该进行更大的全基因组关联研究来证实我们的发现。(C)2018作者（S）由爱思唯尔有限公司出版。这是一篇在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: 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.Methods: 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.Results: 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-DRB1*11: 01 and pruritus (OR = 4.53, X-1,95(2) = 9.45, P < .01) as well as a nominally significant additive association between HLA-DQB1*03:01 and colitis (OR = 3.94, X-1,95(2) = 5.67, P = .017).Conclusions: 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. (C) 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).