Immune Checkpoint Inhibitors-Induced Thyroiditis: Comprehensive Assessment of Underlying Mechanisms
Summary
There is widespread use of immune check point inhibitors (ICIs) in patients with cancer. It is estimated that 45% of patients with cancer in US are eligible for ICIs, including cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor, inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). Wider application of these immunotherapies has also resulted in the emergence of a unique array of immune-related adverse events (irAEs). ICIs frequently cause thyroid dysfunction (10-15%), which is the most common among the endocrine irAEs. Acute destructive thyroiditis characterized by transient thyrotoxicosis followed by recovery or progression to hypothyroidism is seen in 50% -90% of patients who develop ICI-associated thyroid dysfunction.
The underlying mechanism remains unclear, although T cell activation by inhibition of PD-1, PD-L1 or CTLA-4 as well as antibody production by B-cells has been proposed. A recent study noted an increase in the CD4-CD8- T lymphocytes and CD8+ T lymphocytes in the ICI treated thyroid tissue compared to healthy thyroid tissue. However, the study was limited in terms of number of patients and lacked comparison to patients on ICIs who did not develop thyroiditis1. Another study examined the immunophenotype in the peripheral blood flow cytometry in anti PD-1 treated patients and showed phenotypic differences compared with patients with Hashimoto’s thyroiditis2. This study lacks assessment of the thyroid tissue or data on genetic mutations. Pathogenesis of Hashimoto’s thyroiditis includes involvement of B-cells with production of antibodies to thyroglobulin (Anti-TG), thyroid peroxidase (Anti-TPO) and TSH receptor (Anti TSH-R). The T cell mechanisms include involvement of TH-1 cells, TH-2 cells and T regulatory cells. A genetic predisposition in Hashimoto’s thyroiditis incudes several susceptibility genes like Human Leukocyte Antigen (HLA) genes and CTLA-4 gene.
To better understand the mechanisms contributing to the development of thyroiditis, we propose a prospective cohort study to characterize the biochemical, immunological, and genetic characteristics of patients with ICI-associated thyroiditis.
Aims/Methods:
We plan to obtain clinical data and bio specimens from patients on ICIs who: 1) develop thyroiditis (n=15); 2) remain euthyroid (n=15), and 3) have pre-existing Hashimoto’s thyroiditis (n=15). We will obtain serum TSH, FT4, Anti-TPO, Anti-TG, and Anti TSH-R levels; PET CT scan; peripheral blood flow cytometry (to study the subpopulations of lymphocytes and other immune cells); and serum cytokine levels. We will obtain a thyroid needle biopsy for H&E stains, immunophenotype of cell populations by flow cytometry (includes HLA-DR subtype), and PD-L1 level. Finally, we propose testing for genomic data to assess for a mutation panel using genomic sequencing to assess for the presence or absence of certain mutations and their possible association or predisposition to thyroiditis.
Our team (oncology, endocrinology) plans to apply for extramural funding with the preliminary data generated from this project. This study will provide the first comprehensive assessment of patients with ICI-associated thyroiditis. Our innovative approach will result in identifying phenotypic and genetic differences among these patients and may translate to novel immunomodulatory therapies for thyroiditis as well as therapy for advanced thyroid cancer.
References: 1. PMID: 32323619, 2. 28609832
Keywords:
- Cancer
- Chemotherapy