Interleukin 21 drives CXCR6+ CD8+ T cell mediators in Autoimmune Checkpoint Inhibitor Thyroiditis

Checkpoint inhibitor (ICI) immunotherapy leverages the body's own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. To delineate human IRAE pathogenesis, we sampled thyroid tissue from subjects with ICI-thyroiditis and HT. Using single cell RNA sequencing of human thyroid fine needle aspiration (FNA) specimens, we identify CXCR6+ interferon gamma (IFN?)+ cytotoxic CD8+ T cells as key contributors to ICI-thyroiditis (IRAE). This is in contrast to the primary role for CD4+ Th17 cells in the pathogenesis of HT (14, 15). Interestingly, we also found a supporting role for IL21-producing CD4+ T follicular (Tfh) and peripheral helper (Tph) cells via the upregulation of CXCR6 and cytotoxic function in CD8+ T cells. Overall design: This dataset contains a total of 10 single cell transcriptomes (5' and TCR) from human thyroid infiltrating CD45+ immune cells, from 13 individuals with immune checkpoint inhibitor-associated thyroiditis, Hashimoto's thyroiditis, or no thyroid disease, as outlined in the associated manuscript. Specimens were collected by thyroid fine needle aspiration.