Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma

Abstract

// Ziming Du 1 , Malak Abedalthagafi 1 , Ayal A. Aizer 2 , Allison R. McHenry 3 , Heather H. Sun 1 , Mark-Anthony Bray 4 , Omar Viramontes 5 , Revaz Machaidze 1,5 , Priscilla K. Brastianos 6,7 , David A. Reardon 6 , Ian F. Dunn 5 , Gordon J. Freeman 6 , Keith L. Ligon 1,6 , Anne E. Carpenter 4 , Brian M. Alexander 2 , Nathalie Y. Agar 5 , Scott J. Rodig 1 , Elizabeth M. Bradshaw 3 and Sandro Santagata 1,8 1 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA 2 Department of Radiation Oncology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA 3 Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA 4 Imaging Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA 5 Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA 6 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA 7 Department of Neuro-Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 8 Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA Correspondence: Sandro Santagata, email: // Keywords : meningioma, PD-L1, RNAscope, immunotherapy Received : December 15, 2014 Accepted : December 28, 2014 Published : December 31, 2014 Abstract There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma – both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors.