Anupam Kotwal1,2, Michael P Gustafson3,4, Svetlana Bornschlegl3, Lisa Kottschade5, Danae A Delivanis2, Allan B Dietz3, Manish Gandhi3, Mabel Ryder2,5. 1. Division of Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska, USA. 2. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA. 3. Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. 4. Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, Arizona, USA. 5. Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Abstract
Background: 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. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates (n = 9) and peripheral blood (n = 7) as compared with healthy thyroid samples (n = 5) and healthy volunteer blood samples (n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4-CD8- T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8+T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4+PD1+ T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8+PD1+ T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4+CD8+, CD4-CD8- T, gamma-delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: 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.
Background: 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. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates (n = 9) and peripheral blood (n = 7) as compared with healthy thyroid samples (n = 5) and healthy volunteer blood samples (n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4-CD8- T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8+T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4+PD1+ T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8+PD1+ T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4+CD8+, CD4-CD8- T, gamma-delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: 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.
Authors: Danae A Delivanis; Michael P Gustafson; Svetlana Bornschlegl; Michele M Merten; Lisa Kottschade; Sarah Withers; Allan B Dietz; Mabel Ryder Journal: J Clin Endocrinol Metab Date: 2017-08-01 Impact factor: 5.958
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