Investigating Thyroid Disease Associated Systemic Immune Alterations and Implications of Thyroid Hormone Receptor in the Ovarian Tumour Immune Microenvironment

Abstract

Chronic inflammation has been associated with the development and progression of epithelial ovarian cancer (EOC). In this study, we aimed to address how a common endocrine disorder, hypothyroidism, can promote inflammation and potentially alter the immune infiltration within EOC tumours and female patients. Using immunohistochemistry, we identified varied expression of thyroid hormone receptor alpha (THRalpha) in EOC cells. Expression of this receptor was negatively correlated with disease-specific survival among clear cell ovarian cancer (CCOC) patients but not with high-grade serous ovarian cancer (HGSC) patients. High THRalpha expression in CCOC tumours was positively correlated with immune exhaustion, as demonstrated by increased programmed death protein 1 (PD-1) expression. CD68+ cells, most likely representing macrophages, were negatively associated with THR expression in HGSC tumours, displaying the potential for altered thyroid hormone signalling to influence the type of immune cell infiltration present within these tumours. To further assess the role of hypothyroidism in promoting pro-tumorigenic inflammation, we investigated how hypothyroidism can alter the circulating immune cell profiles in young adult female patients. By studying the immune cell population differences between female patients with hypothyroidism compared to their healthy controls, we observed a significant increase in myeloid cell populations in these patients, likely representing a downstream consequence of the increased inflammation resulting from hypothyroidism. Several helper T cell populations and CD19+ B cells were slightly increased in the hypothyroid group, aligning with existing evidence associated with the immunological effects associated with autoimmune related thyroid disease. Additionally, we demonstrated that these differences were not associated with high thyroid stimulating hormone (TSH) levels, suggesting that the differences in immune cell profiles were present in patients with hypothyroidism regardless of treatment with exogenous thyroid hormone. These differences in immune cell profiles could potentially alter the nature of the cancer and response to treatment. Increasing evidence in the field has shown that high pre-diagnosis inflammatory scores in EOC patients are associated with poor overall survival. As such, our study highlights how hypothyroidism may be a factor contributing to chronic inflammation and altered treatment responses in some patients with EOC, thus illustrating a key area of research requiring further investigation.