PD-L1 expression in medulloblastoma: an evaluation by subgroup
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Allison M. Martin1, Christopher J. Nirschl2, Magda J. Polanczyk1, W Robert Bell3, Thomas R. Nirschl4, Sarah Harris-Bookman5, Jillian Phallen6, Jessica Hicks7, Daniel Martinez8, Aleksandra Ogurtsova9, Haiying Xu9, Lisa M. Sullivan10, Alan K. Meeker7, Eric H. Raabe1,11, Kenneth J. Cohen1, Charles G. Eberhart11, Peter C. Burger11, Mariarita Santi8, Janis M. Taube9, Drew M. Pardoll2, Charles G. Drake12 and Michael Lim13
1Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA
2Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA
3Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA
4Johns Hopkins School of Medicine, Department of Pathobiology, Baltimore, MD, USA
5Johns Hopkins School of Medicine, Department of Ophthalmology, Baltimore, MD, USA
6Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Biology, Baltimore, MD, USA
7Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA
8Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA
9Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA
10In Jackson, MS, USA
11Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA
12Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA
13Johns Hopkins School of Medicine, Department of Neurosurgery, Division of Neurosurgical Oncology, Baltimore, MD, USA
Allison M. Martin, email: [email protected]
Keywords: medulloblastoma; PD-1; brain tumor; PD-L1; B7-H1
Received: August 03, 2017 Accepted: March 13, 2018 Published: April 10, 2018
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, TH1 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.
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