Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

// Yu Mei 1* , Wenya Linda Bi 1,2* , Noah F. Greenwald 1,2 , Ziming Du 3 , Nathalie Y.R. Agar 1,2 , Ursula B. Kaiser 4 , Whitney W. Woodmansee 4 , David A. Reardon 5 , Gordon J. Freeman 5 , Peter E. Fecci 6,7 , Edward R. Laws Jr 1 , Sandro Santagata 2,3 , Gavin P. Dunn 8,9 and Ian F. Dunn 1 1 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 3 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 4 Division of Endocrinology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 6 Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA 7 Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA 8 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA 9 Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA * These authors contributed equally to this work Correspondence to: Ian F. Dunn , email: // Gavin P. Dunn, email: // Keywords : pituitary adenoma, PD-L1, RNAscope, checkpoint inhibition, immunotherapy Received : May 06, 2016 Accepted : August 25, 2016 Published : September 17, 2016 Abstract Purpose: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.