Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). Experimental Design: In patients with non–small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52–0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29–1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08–1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. Conclusions: Thyroid irAEs were associated with response to anti–PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.

中文翻译：

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免疫治疗介导的甲状腺功能障碍：非小细胞肺癌中 PD-1 阻断对结果的遗传风险和影响

目的：免疫的遗传差异可能导致免疫检查点抑制剂 (CPI) 治疗的毒性和结果，但这些关系知之甚少。我们检查了甲状腺免疫相关不良事件 (irAE) 的遗传学。实验设计：在纪念斯隆凯特琳 (MSK) 和范德比尔特大学医学中心 (VUMC) 接受 CPI 治疗的非小细胞肺癌 (NSCLC) 患者中，我们评估了甲状腺 irAE。我们使用全基因组单核苷酸多态性 (SNP) 阵列和估算的基因型对种系 DNA 进行分型。Germline SNP 插补也在一个独立的 Dana-Farber 癌症研究所 (DFCI) 队列中进行。我们使用英国和 VUMC BioVU 生物库开发并验证了非癌症患者甲状腺功能减退症的多基因风险评分 (PRS)。这些 PRS 应用于 MSK、VUMC 和 DFCI 的 NSCLC 患者的甲状腺 irAE 和 CPI 反应。结果：在 MSK 和 VUMC 的 744 名患者中，甲状腺 irAE 发生率为 13%，并且与改善的结果相关[无进展生存调整 HR (PFS aHR) = 0.68；95% 置信区间 (CI), 0.52–0.88]。从 UK Biobank 开发的甲状腺功能减退 PRS 在 BioVU 数据集中预测非癌症患者的甲状腺功能减退 [OR 每标准差 (SD) = 1.33, 95% CI, 1.29–1.37; AUROC = 0.6]。相同的 PRS 还预测了接受 CPI 治疗的两个独立患者队列中甲状腺 irAE 的发展（HR/SD = 1.34；95% CI，1.08-1.66；AUROC = 0.6）。DFCI 队列中的结果相似。然而，甲状腺功能减退的 PRS 并不能预测 CPI 的获益。结论：甲状腺 irAE 与抗 PD-1 治疗的反应相关。甲状腺功能减退的遗传风险与发生甲状腺 irAE 的风险相关。需要进一步的研究来确定其他 irAE 是否也与已知的自身免疫性疾病具有共同的遗传风险以及与治疗反应的关联。