Abstract
BACKGROUND: Cushing’s disease (CD) is caused by an ACTH-secreting pituitary adenoma that causes severe patient morbidity. First-line treatment for CD is surgical adenomectomy, but 25% of these patients will recur within 5-years. Targeting immune checkpoint Program Death Ligand-1 (PDL1) has emerged as a viable immunotherapeutic approach. The expression of PD-L1 on pituitary adenomas is recently demonstrated by our group and others, making PD-L1 a potential immunologic target. METHODS: Immunohistochemistry (IHC) was used to determine the expression of PD-L1 on 19 human pituitary adenoma samples, including 9 ACTH-secreting adenomas. For murine in-vitro studies, the ACTH-secreting pituitary adenoma ATT20/D16v.2 cell line was assessed by flow cytometry. For in-vivo studies, a murine-model of CD was established. ATT20/D16v.2 cells were implanted into the flank of A/HeJ x C57L/J F1 mice, and continued PD-L1 expression confirmed on harvested tumors. Plasma ACTH was assessed by EIA at baseline and 6-weeks after tumor implantation. Tumor-bearing mice were then treated intraperitoneally(i.p.) with anti-PDL1 or isotype control every 3 days x 12 doses. Tumor volume, mouse weight, and ACTH levels were assessed. RESULTS: Our data reveal the upregulated expression of ACTH-secreting PD-L1 on pituitary adenomas of both patients and mice compared to normal pituitary. Human pituitary adenomas demonstrate significant (i.e.≥1% staining) PD-L1 expression in 32% of samples, including 22% of ACTH-secreting adenomas. Similar findings are observed in mice, where the ATT20/D16v.2 cell line, as well as tumor grown subcutaneously in flank both demonstrates elevated PD-L1 expression, as well as elevated plasma ACTH concentration. Anti-PDL1 treated mice demonstrated significant reductions to both tumor volume and plasma ACTH levels. CONCLUSIONS: PD-L1 is found significantly elevated on ACTH-secreting pituitary adenomas in patients and mice. Furthermore, there is a significant antitumor effect with the administration of anti-PDL1. These results demonstrate a promising immunotherapeutic approach for CD. A multi-institution clinical trial is being planned.