PD-L1 expression in medulloblastoma: An evaluation by subgroup

// Allison M. Martin 1 , Christopher J. Nirschl 2 , Magda J. Polanczyk 1 , W Robert Bell 3 , Thomas R. Nirschl 4 , Sarah Harris-Bookman 5 , Jillian Phallen 6 , Jessica Hicks 7 , Daniel Martinez 8 , Aleksandra Ogurtsova 9 , Haiying Xu 9 , Lisa M. Sullivan 10 , Alan K. Meeker 7 , Eric H. Raabe 1, 11 , Kenneth J. Cohen 1 , Charles G. Eberhart 11 , Peter C. Burger 11 , Mariarita Santi 8 , Janis M. Taube 9 , Drew M. Pardoll 2 , Charles G. Drake 12 and Michael Lim 13 1 Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA 2 Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA 3 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA 4 Johns Hopkins School of Medicine, Department of Pathobiology, Baltimore, MD, USA 5 Johns Hopkins School of Medicine, Department of Ophthalmology, Baltimore, MD, USA 6 Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Biology, Baltimore, MD, USA 7 Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA 8 Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA 9 Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA 10 In Jackson, MS, USA 11 Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA 12 Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA 13 Johns Hopkins School of Medicine, Department of Neurosurgery, Division of Neurosurgical Oncology, Baltimore, MD, USA Correspondence to: Allison M. Martin, email: amarti65@jhmi.edu Keywords: medulloblastoma; PD-1; brain tumor; PD-L1; B7-H1 Received: August 03, 2017      Accepted: March 13, 2018      Published: April 10, 2018 ABSTRACT Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro , IFN-γ robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-γ), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, T H 1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.