Abstract
BACKGROUND: Immunotherapies and targeted therapies are frequently associated with thyroid dysfunction, which is in contrast with the rare thyroid abnormalities induced by cytotoxic agents. Immunotherapy with NY-ESO-1, a tumor-associated antigen expressed by a number of malignancies, was reported to trigger hyperthyroidism or hypothyroidism in two HLA-A2 patients with ovarian cancer. We describe now a case of Graves' disease triggered by NY-ESO-1 in a HLA-A2-negative woman. PATIENT FINDINGS: A 32-year-old woman with a synovial sarcoma received radiotherapy, chemotherapy, and finally NY-ESO-1 vaccine. The patient was found to have HLA A11/A33(19), B13/B56(22), Cw3/-. One month after the beginning of immunotherapy, thyroid dysfunction was clinically suspected and Graves' disease was biochemically confirmed. Fearful of the antithyroid drugs' side effects, the patient was treated with a beta-blocker (propranolol, 80-20 mg/day). As hyperthyroidism progressively worsened, the patient underwent total thyroidectomy. We hypothesized that NY-ESO-1 shared partial homology with thyroid autoantigens (the so-called molecular mimicry mechanism) and that at least one pair of homologous sequences contained amino acid sequence binding motifs to a restricted number of HLA molecules. We used BLAST software to search amino acid sequence homologies between NY-ESO-1 and thyroid autoantigens (thyrotropin receptor [TSH-R], thyroperoxidase, and thyroglobulin), and the HLA ligand/motif database to look for HLA/T-cell receptor binding motifs in the regions of NY-ESO-1 and thyroid autoantigens that were homologous. We found 15 epitopic regions of NY-ESO-1 homologous to 15 regions of thyroid autoantigens, some of which epitopic: 5 of TSH-R, 8 of thyroglobulin, and 2 of thyroperoxidase. These homologous sequences contain binding motifs belonging to several HLA class I antigens, including HLA A2 and the patient's A11 and A33. SUMMARY: Genetically predisposed patients who receive NY-ESO-1 vaccination are at risk to develop thyroid dysfunction. CONCLUSIONS: Considering the increasing use of NY-ESO-1, thyroid dysfunctions induced by NY-ESO-1 are expected to increase in cancer patients over the next years.