The Pituitary Immune Environment and Immunotherapy: From Hypophysitis to Pituitary Neuroendocrine Tumors

Abstract

The immune landscape plays an important role in various pituitary diseases, ranging from hypophysitis to pituitary neuroendocrine tumors. Moreover, the use of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of cancer treatment by improving prognosis and overall survival in a multitude of advanced-staged malignancies, though their use in pituitary neuroendocrine tumors has remained limited. In this review, we will focus on selected topics to highlight the impact of the immune microenvironment on the function of the pituitary gland, namely, animal models of autoimmune hypophysitis, including ICI-induced hypophysitis as a common adverse event, and the importance of its early recognition in patients treated with ICIs. Using a case, we will provide an overview on the epidemiology, pathogenesis, clinical spectrum, diagnosis, predictors, and management of ICI-induced hypophysitis. We will also summarize the role of the immune microenvironment in pituitary neuroendocrine tumors with programmed cell death ligand 1 as a biomarker for treatment. Lastly, we will review the role of ICIs in the management of 40 patients with aggressive and metastatic pituitary neuroendocrine tumors. Current knowledge gaps in these topics will also be highlighted.

Keywords: aggressive pituitary neuroendocrine tumors; hypophysitis; immune checkpoint inhibitors; immune microenvironment; immunotherapy; programmed cell death ligand 1.

Figure 1

Immune cell infiltrates in pituitary macroadenoma and microadenomas. A T1-weighted MR image shows a macroadenoma ((a); null cell adenoma, arrow), which photomicrograph demonstrates scattered CD68+ macrophages (c), rare CD4+ cells (e), and rare CD8+ cells (g). In contrast, a Gadolinium-enhanced T1-weighted MR image exhibits a microadenoma ((b); ACTH adenoma, arrow) which photomicrograph demonstrates sparse CD68+ macrophages (d), rare CD4+ cells (f), and rare CD8+ cells (h). Original magnifications ×400 (c–h). Reproduced with permission from [44] Springer Nature: Lu JQ/Chik CL, et al. Endocrine Pathology 2015;26:263-72.