Abstract
Background: Immune-related adverse events by immune checkpoint inhibitors often involve several endocrine-related organs. PD-1 pathway blockade therapy by anti-PD-1 antibodies including nivolumab frequently causes thyroid dysfunction (thyroid irAE). Thyroid irAE seems to be distinctive compared to conventional painless thyroiditis in terms of a clinical course: transient thyrotoxicosis and subsequent persistent hypothyroidism [1]. Our retrospective cohort study regarding nivolumab provided several suggestions [2]. The thyroid irAE (+) group had a longer median overall survival than the thyroid irAE (−) group in patients with lung cancer, but this observation was not seen in patients with malignant melanoma: In addition, 5 of 17 patients tested at the point of thyroid dysfunction development were double negative for TPOAbs and TgAbs, known thyroid autoantibodies. From these findings, we set a hypothesis that antibodies for unknown antigens mediate prognostic effects of thyroid irAEs if tumor tissues express the same antigens. Methods: We performed co-immunoprecipitation using Protein G beads, sera of three patients with thyroid irAEs, and lysates of HEK293T cells overexpressing candidate proteins tagged with FLAG and HiBit (NKX2-1, PAX8, FOXE1, and HHEX). The pellets were analyzed by western blot. Results: FOXE1 bands were augmented in patient 1 with lung cancer, a PAX8 band in patient 2 with malignant melanoma, and bands of FOXE1, PAX8, and HHEX in patient 3 with renal cell carcinoma, compared to a control sample of a normal subject. We performed subcutaneous injections of purified IgG fraction from the serum of patient 3 to C57BL/6 mice every 2 weeks. The mice were sacrificed after 4 weeks, but no significant changes were observed in their thyroid glands and thyroid function. Conclusions: We identified novel autoantibodies for FOXE1, PAX8, and HHEX, thyroid-specific transcriptional factors. In our experiments, the pathogenicity of antibodies were not suggested. Considering our previous observation that the thyroid gland expresses both PD-L1 and PD-L2, ligands of PD-1 receptor [1], PD-1 pathway blockade may particularly disrupt immune tolerance of the thyroid gland, resulting in autoantibody production. Because thyroid irAEs have been revealed to be a prognostic factor, these novel autoantibodies are candidate biomarkers for PD-1 pathway blockade therapy. References: 1. Yamauchi et al. Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. Thyroid. 2017; 27(7): 894–901. 2. Yamauchi et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS One. 2019; 14(5): e0216954.
Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently evoked in Japanese patients with malignant melanoma