Immune Checkpoint Inhibitor-Induced Thyroiditis Is Associated with Increased Intrathyroidal T Lymphocyte Subpopulations

<b><i>Background:</i></b> Immune checkpoint inhibitors (ICIs) frequently cause thyroid dysfunction but their underlying mechanism remains unclear. We have previously demonstrated increased circulating natural killer (NK) cells and human leukocyte antigen (HLA)-DR surface expression on inflammatory intermediate CD14⁺CD16⁺ monocytes in programmed cell death protein-1 (PD-1) inhibitor-treated patients. This study characterizes intrathyroidal and circulating immune cells and class II HLA in ICI-induced thyroiditis. <b><i>Methods:</i></b> This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates (<i>n</i> = 9) and peripheral blood (<i>n</i> = 7) as compared with healthy thyroid samples (<i>n</i> = 5) and healthy volunteer blood samples (<i>n</i> = 44); HLA class II was tested in <i>n</i> = 9. <b><i>Results:</i></b> ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, <i>p</i> = 0.00006), CD4^-CD8^- T lymphocytes (1.9% vs. 0.7%, <i>p</i> = 0.006), and, as a percent of T lymphocytes, increased CD8⁺T lymphocytes (38.6% vs. 25.7%; <i>p</i> = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4⁺PD1⁺ T lymphocytes (40.4% vs. 0.8%; <i>p</i> = 0.021) and CD8⁺PD1⁺ T lymphocytes (28.8% vs. 1.5%; <i>p</i> = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4⁺CD8⁺, CD4^-CD8^- T, gamma<b>-</b>delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. <b><i>Conclusions:</i></b> ICI-induced thyroiditis is a T lymphocyte-mediated process with intra-thyroidal predominance of CD8⁺ and CD4^-CD8^- T lymphocytes. The HLA haplotypes may be involved but need further evaluation. These findings expand the limited understanding of ICI-induced thyroiditis, which could be further translated to guide immunomodulatory therapies for advanced thyroid cancer.