ytotoxic T lymphocyte-associated protein 4 (CTLA4) is overexpressed in a subset of prolactin- and growth hormone-secreting pituitary adenomas

Cytotoxic T lymphocyte-associated protein 4 (CTLA4), a negative regulator typically expressed on the surface of T lymphocytes, is targeted by immunotherapy in patients with an ever-expanding spectrum of cancers. Characterizing the expression of CTLA4 in the pituitary gland could provide additional rationale for using immune checkpoint inhibitors in pituitary adenoma patients who do not respond to conventional treatments. We assessed the expression of CTLA4 mRNA and protein in a panel of 157 human pituitary glands, 45 collected at autopsy and 112 at surgery. These specimens included 50 normal glands and 107 adenomas: 41 nonsecreting, 25 PRL-, 24 ACTH-, 11 GH-, 2 TSH-, 1 FSH-secreting, and 3 atypical. Specimens were stained for CTLA4 and adenohypophyseal hormones using RNAscope in situ hybridization, immunohistochemistry, and RNAscope Multiplex Fluorescent Assay. CTLA4 mRNA was detectable in most normal pituitary glands (48 of 50, 96%) but varied in expression, with a histological score (H-score) ranging from 0.6 to 20. The variation did not depend upon the patient's gender and age and was not significantly affected by the archival storage time. CTLA4 expression was higher (P = 0.022) in pituitary adenomas than normal glands, with the greatest levels seen in PRL- and GH-secreting adenomas (P = 0.009 and 0.023 versus normal, respectively). Eight of 25 (32%) prolactinomas and 3 of 11 (27%) GH-adenomas had an H-score greater than 20, while no differences were seen for the other types. These novel data highlight the expression of an immune checkpoint such as CTLA4 on pituitary endocrine cells, a finding that could be exploited for therapeutical applications.