发表刊物：Frontiers in Immunology（IF=5.7）
研究背景
免疫检查点抑制剂（ICIs）如PD-1抑制剂在癌症治疗中取得显著疗效，但也可能引发免疫相关不良事件（irAEs）。免疫相关甲状腺功能障碍（irTD）是最常见的内分泌irAE之一，包括甲状腺功能亢进（甲亢）和甲状腺功能减退（甲减）。irTD患者可能无症状或表现为非特异性症状（如心悸、疲劳），易与癌症进展混淆，导致漏诊风险增加。部分患者确诊时已出现不可逆损伤，严重者可能危及生命。因此，早期预测和干预至关重要。
目前研究多聚焦于治疗前生物标志物（如基线甲状腺抗体或炎症指标）的预测价值，但PD-1抑制剂通过调节免疫微环境（如基因表达、免疫细胞亚群组成）诱导irTD，治疗早期的免疫动态变化可能提供更优的预测信息。此外，细胞因子在irAEs预测中的作用已有验证，但针对irTD的研究有限。本研究首次探讨PD-1抑制剂治疗早期阶段的生物标志物（血液指标和细胞因子）对irTD的预测能力。
2024年10月，中国人民解放军总医院王天琳团队发表在《Frontiers in Immunology》上的研究揭示了PD-1抑制剂治疗早期阶段的生物标志物（如IL-16、IL-12p70等）对免疫相关甲状腺功能障碍（irTD）的预测能力。该研究为irTD的早期识别和干预提供了重要依据，具有显著的临床意义。
研究结果分析
1. 患者特征与irTD发生率
264例患者中，irTD发生率为21.97%（58例），其中甲亢占53.4%（31例），甲减占46.6%（27例）。两组在性别、年龄、肿瘤类型、PD-1抑制剂种类及联合治疗方案上无显著差异（P>0.05）。甲状腺功能变化：早期治疗阶段，irTD组的TSH显著降低（P=0.000），TgAb和TPOAb阳性率显著高于非irTD组（P=0.000）。
2.早期生物标志物的预测优势
多因素逻辑回归：早期阶段的TgAb（OR=2.831, 95%CI:1.077-7.443, P=0.035）和TPOAb（OR=9.565, 95%CI:3.399-26.921, P=0.000）是irTD的独立预测因子。
ROC曲线分析：
irTD整体预测：早期生物标志物AUC为0.655，显著优于治疗前的0.571。甲亢预测：早期TSH降低（OR=0.162, 95%CI:0.077-0.341, P=0.000）的AUC为0.812，显著高于治疗前的0.637。甲减预测：女性（OR=3.889, 95%CI:1.457-10.380, P=0.007）和早期TPOAb阳性（OR=8.678, 95%CI:2.656-28.357, P=0.000）的AUC为0.728，略优于治疗前的0.710。
3. 抗体芯片筛选早期治疗生物标志物
抗体芯片：利用RayBio QAH-CAA-2000抗体芯片（检查人类样本120种验证及免疫相关细胞因子），筛选与irTD相关的差异性细胞因子。
差异表达分析：早期治疗阶段，irTD组11种细胞因子显著升高（如IL-16、IL-12p70、IL-17、CCL-15、IL-1a），CXCL16降低。
关键细胞因子：IL-16（校正P=0.004）、IL-12p70（校正P=0.014）、IL-17（校正P=0.014）、CCL-15（校正P=0.014）、IL-1a（校正P=0.021）在irTD组早期显著升高，且与治疗前相比差异显著（P<0.05）。
上述细胞因子与CD4+ T细胞分化（Th1/Th17）及自身免疫性甲状腺炎机制相关（如IL-17促进炎症反应，IL-12驱动Th1极化）。
讨论与总结
研究团队首次证实PD-1抑制剂治疗早期的生物标志物（TgAb、TPOAb及特定细胞因子）对irTD具有显著预测价值，其效能优于治疗前指标。早期TSH降低和TPOAb阳性分别对甲亢和甲减的预测效能突出（AUC>0.7）。此外，IL-16、IL-12p70等细胞因子的发现为irTD机制研究提供了新方向，提示Th1/Th17免疫轴可能参与发病。
总之，本研究为irTD的早期预测提供了重要依据，并强调了治疗早期免疫动态监测的临床价值。通过优化生物标志物检测策略，有望改善免疫治疗的安全性管理，提升患者生活质量。
文章信息：Fava A, Buyon J, Magder L, Hodgin J, Rosenberg A, Demeke DS, Rao DA, Arazi A, Celia AI, Putterman C, Anolik JH. Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis. JCI insight. 2024 Jan 1;9(2).
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