Overrepresentation of highly functional T regulatory cells in patients with nonfunctioning pituitary adenoma

Nonfunctioning pituitary adenoma is a common intracranial tumor. Though benign in the majority of cases, complications can be excruciating to the affected individual, and recurrences after tumor removal may happen with more aggressive clinical features. T regulatory (Treg) cells are generally considered a tumor-promoting immune cell type in malignant cancers with currently unclear roles in pituitary adenoma patients. Therefore, we investigated the frequency and functional characteristics of Treg cells in nonfunctioning pituitary adenoma patients before and after tumor removal. Compared to healthy controls, untreated patients with nonfunctioning pituitary adenomas presented an overrepresentation of highly functional circulating FOXP3⁺ Treg cells. Specifically, the FOXP3⁺ Treg cells in patients were slightly upregulated in frequency and displayed markedly elevated capacity to co-produce TGF-β and IL-10. TIM-3 is a negative regulator of proinflammatory immune responses and is expressed by highly activated Treg cells. In both healthy controls and pituitary adenoma patients, TIM-3⁺ Treg cells presented significantly higher levels of TGF-β and IL-10 co-producing cells than TIM-3^- Treg cells but compared to healthy controls, patients with nonfunctioning pituitary adenomas showed significantly higher levels of TIM-3⁺ FOXP3⁺ Treg cells. Interestingly, surgical removal of the tumor significantly reduced the extent of Treg upregulation in patients. Also, resected pituitary adenomas contained highly functional FOXP3⁺ Treg cells, with high levels of TIM-3 expression and high frequency of TGF-β and IL-10 co-producers in the TIM-3⁺ fraction. Overall, these results demonstrate that patients with nonfunctioning pituitary adenomas are characterized by an overrepresentation of highly functional Treg cells.