Transcriptomic signatures associated with autoimmune thyroiditis in papillary thyroid carcinoma and cancer immunotherapy-induced thyroid dysfunction

Up to 20% of patients treated with anti-PD-1/PD-L1 inhibitors suffered from thyroid dysfunctions, yet the mediators associated with their occurrence remain unclear. The increasing coincidence of papillary thyroid carcinoma (PTC) with Hashimoto thyroiditis (HT) and the high vulnerability of thyroid to immunotherapy motivated us to discover the similarities and their underlying transcriptomic basis. Clinical characteristics analysis of 468 PTC patients from two independent cohorts and meta-analysis of 22,155 PTC patients unveiled a strong negative association between HT and recurrence in PTC patients. Transcriptome analysis of both cohorts showed PTC patients with HT were enriched in macrophages, CD8(+) and CD4(+) cytotoxic T cells, which was further validated by single-cell transcriptome analysis of 17,438 cells from PTC patients, and CD8(+) T cells were correlated with disease-free survival of PTC patients. In both cohorts and single-cell dataset, elevated expression of PD-1-related genes was observed in the HT group, and CD3D appeared to be a target for enhancing the activation of CD8(+) T cells. Correlation analysis of 3,318 thyroid adverse events from 39,123 patients across 24 tumor types and molecular signatures demonstrated similar signatures associated with autoimmune thyroiditis in PTC and thyroid immune-related adverse events (irAEs), and several multi-omics signatures, including signatures of CD8A and CD8(+) T cells, showed positive associations with the odds ratio of thyroid irAEs. Our results unveil shared molecular signatures underlying thyroid dysfunction between patients receiving immunotherapies and PTC patients suffering from HT, which may shed light on managing the adverse events during cancer immunotherapy.