Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-006570.
Immune checkpoint inhibitors (ICIs) have dramatically improved survival in patients with cancer but are often accompanied by severe immune-related adverse events (irAEs), which can sometimes be irreversible. Insulin-dependent diabetes is a rare, but life-altering irAE. Our purpose was to determine whether recurrent somatic or germline mutations are observed in patients who develop insulin-dependent diabetes as an irAE.
We performed RNA and whole exome sequencing on tumors from 13 patients who developed diabetes due to ICI exposure (ICI-induced diabetes mellitus, ICI-DM) compared with control patients who did not develop diabetes.
In tumors from ICI-DM patients, we did not find differences in expression of conventional type 1 diabetes autoantigens, but we did observe significant overexpression of ORM1, PLG, and G6PC, all of which have been implicated in type 1 diabetes or are related to pancreas and islet cell function. Interestingly, we observed a missense mutation in NLRC5 in tumors of 9 of the 13 ICI-DM patients that was not observed in the control patients treated with the same drugs for the same cancers. Germline DNA from the ICI-DM patients was sequenced; all mutations were germline. The prevalence of germline variants was significantly greater than the general population (p=5.98×10). Although NLRC5 is implicated in development of type 1 diabetes, germline mutations were not found in public databases from patients with type 1 diabetes, suggesting a different mechanism of insulin-dependent diabetes in immunotherapy-treated patients with cancer.
Validation of the mutation as a potential predictive biomarker is warranted, as it might improve patient selection for treatment regimens. Furthermore, this genetic alteration suggests potential mechanisms of islet cell destruction in the setting of checkpoint inhibitor therapy.
免疫检查点抑制剂 (ICIs) 显著改善了癌症患者的生存率，但常伴有严重的免疫相关不良事件 (irAEs)，有时甚至是不可逆的。胰岛素依赖型糖尿病是一种罕见但改变生活的 irAE。我们的目的是确定在因 ICI 暴露而发生胰岛素依赖型糖尿病的患者 (ICI 诱导的糖尿病，ICI-DM) 中是否观察到复发性体细胞或种系突变。
我们对 13 例因 ICI 暴露而发生糖尿病的患者（ICI-DM 患者）的肿瘤进行了 RNA 和全外显子测序，与未发生糖尿病的对照患者进行了比较。
在 ICI-DM 患者的肿瘤中，我们没有发现传统 1 型糖尿病自身抗原表达的差异，但我们确实观察到 ORM1、PLG 和 G6PC 的显著过表达，这些都与 1 型糖尿病有关，或与胰腺和胰岛细胞功能有关。有趣的是，我们在 13 例 ICI-DM 患者的肿瘤中观察到 NLRC5 中的错义突变，而在接受相同药物治疗相同癌症的对照患者中未观察到该突变。对 ICI-DM 患者的种系 DNA 进行测序；所有突变均为种系突变。种系变体的患病率明显高于一般人群 (p=5.98×10)。尽管 NLRC5 与 1 型糖尿病的发生有关，但在来自 1 型糖尿病患者的公共数据库中未发现种系突变，这表明在接受癌症免疫治疗的患者中，胰岛素依赖型糖尿病存在不同的发病机制。
验证 突变作为潜在的预测生物标志物是合理的，因为它可能改善患者对治疗方案的选择。此外，这种遗传改变提示了在检查点抑制剂治疗中胰岛细胞破坏的潜在机制。
