PD-1-Ab therapeutic hypothyroidism associated with decreased of peripheral blood CD4 ⁺ T cells and addressed prophylactic medication of thyroxine administration

Immune checkpoint inhibitor PD-1 antibody (PD-1-Ab) has arisen the increasing clinical prevalence of immune-related adverse events (irAEs) such as hypothyroidism. Hypothyroidism is the common irAEs, but the mechanism of such immunological pathogenesis was still unclear. We have developed a unique hypothyroidism mice model induced by mimicking clinical exposure to PD-1-Ab. Then we analyzed the immune cell phenotypes in the peripheral blood of mouse models by flow cytometry and further verified in patients' samples. Therefore, we have further investigated the molecular pathogenesis of such condition through the spatial transcriptome sequencing in thyroid glands. Those findings have supported the recommendations of prophylactic treatment with thyroxine in a very beginning timepoint. The results showed that the CD4⁺T-cell subset declined in the peripheral blood of hypothyroidism mice induced by PD-1-Ab, which was consistent with the similarities in the patients with hypothyroidism. Moreover, spatial transcriptome sequencing of thyroid glands of mice was predominantly featured by upregulated IL-17 signaling pathway and involved endoplasmic reticulum stress, which provided the evidences to address the preliminary roles of immunological pathogenesis participated. In addition, we have demonstrated that a combination with early onset of thyroxine supplements could prevent the subsequent occurrence of hypothyroidism. Those experimental and clinical data provided the awareness that CD4⁺T cells are associated with hypothyroidism caused by PD-1-Ab, and therefore, prophylactic administration of thyroxine should be considered with great caution and in timely manner.<b>NEW & NOTEWORTHY</b> This study explored the immunopathogenic mechanism of immune checkpoint inhibitor associated hypothyroidism through T-cell phenotype and spatial transcriptome sequencing of thyroid glands of mimicked mice model. The findings revealed decreased CD4⁺T-cell subset and subsequently featured by upregulated IL-17 signaling pathway. The prophylactic thyroxine was recommended in the early onset of hypothyroidism.