Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China; Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
Eur J Cancer. 2023 May;184:124-136. doi: 10.1016/j.ejca.2023.01.034. Epub 2023 Feb 23.
PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs). The host immunogenetic background is likely to play a role in irAE susceptibility. In this study, we aimed to identify potential immunogenetic biomarkers to predict irAEs.
Patients with solid tumours receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumour-immunity and autoimmune diseases were screened out via protein-protein interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between genetic variants and irAEs as well as irAEs-free survival was performed.
Four immunogenetic variants as predictive biomarkers of irAEs were identified. The C allele of Mitogen-Activated Protein Kinase 1 (MAPK1) rs3810610 (odds ratio [OR] = 1.495, 95% confidence interval [CI] = 1.093-2.044, P = 0.012) was a risk predictor while the A allele of PTPRC rs6428474 (OR = 0.717, 95% CI = 0.521-0.987, P = 0.041) was a protective factor for all-grade irAEs. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355-4.983, P = 0.003) increased the risk while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205-0.881, P = 0.018) protected patients from high-grade irAEs. Significant immunogenetic variants reached a similar tendency in PD-1 blockade or lung cancer subgroups. In multivariate Cox regression analysis, the MAPK1 rs3810610 was an independent factor regarding all-grade irAEs-free survival (CC versus CT or TT: hazard ratio [HR] = 0.71, 95% CI = 0.52-0.99, P = 0.042). ADAD1 rs17388568 (AA versus AG or GG: HR = 0.11, 95% CI = 0.025-0.49, P = 0.004) and IL6 rs1800796 (GG or GC versus CC: HR = 3.10, 95% CI = 1.315-7.29, P = 0.01) were independent variables for high-grade irAEs-free survival.
We first identified several immunogenetic polymorphisms associated with irAEs and irAEs-free survival in PD-1/PD-L1 blockade-treated tumour patients, and they may serve as potential predictive biomarkers.
PD-1/PD-L1 抑制剂带来了显著的疗效，但也会引发严重的免疫相关不良事件（irAEs）。宿主的免疫遗传背景可能在 irAE 易感性中起作用。本研究旨在寻找潜在的免疫遗传生物标志物来预测 irAEs。
招募了接受 PD-1/PD-L1 阻断治疗的实体瘤患者，并进行了随访。通过蛋白质-蛋白质相互作用网络和 Cytoscape 筛选出被认为对肿瘤免疫和自身免疫性疾病有重要贡献的基因。随后，使用多重基因分型检测对 18 个基因中的 39 个变体进行了基因分型。对遗传变异与 irAEs 以及 irAEs 无进展生存之间的相关性进行了分析。
确定了四个免疫遗传变异作为 irAEs 的预测生物标志物。MAPK1 基因 rs3810610 的 C 等位基因（OR=1.495，95%CI=1.093-2.044，P=0.012）是 irAEs 的风险预测因子，而 PTPRC 基因 rs6428474 的 A 等位基因（OR=0.717，95%CI=0.521-0.987，P=0.041）是所有等级 irAEs 的保护因素。ADAD1 基因 rs17388568 的 A 等位基因（OR=2.599，95%CI=1.355-4.983，P=0.003）增加了风险，而 IL6 基因 rs1800796 的 G 等位基因（OR=0.425，95%CI=0.205-0.881，P=0.018）则保护患者免受高级别 irAEs 的影响。在 PD-1 阻断或肺癌亚组中，有意义的免疫遗传变异也呈现出相似的趋势。多变量 Cox 回归分析显示，MAPK1 rs3810610 是所有等级 irAEs 无进展生存的独立因素（CC 与 CT 或 TT：HR=0.71，95%CI=0.52-0.99，P=0.042）。ADAD1 rs17388568 的 AA 等位基因（AA 与 AG 或 GG：HR=0.11，95%CI=0.025-0.49，P=0.004）和 IL6 rs1800796 的 GG 或 GC 等位基因（GG 或 GC 与 CC：HR=3.10，95%CI=1.315-7.29，P=0.01）是高级别 irAEs 无进展生存的独立变量。
我们首次发现了与 PD-1/PD-L1 阻断治疗的肿瘤患者的 irAEs 和 irAEs 无进展生存相关的几个免疫遗传多态性，它们可能作为潜在的预测生物标志物。
