title: Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.
abstract: OBJECTIVE
  Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice.
  
  
  RESULTS
  Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment.
  
  
  CONCLUSIONS
  This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment.
authors.affiliation: Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida. Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christina D
authors.initials: CD
authors.lastname: Pham
authors.affiliation: Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida.
authors.forename: Catherine
authors.initials: C
authors.lastname: Flores
authors.affiliation: Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida.
authors.forename: Changlin
authors.initials: C
authors.lastname: Yang
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Pinheiro
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida. Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Sayour
authors.affiliation: Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Colin
authors.initials: C
authors.lastname: Moore
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida.
authors.forename: Jianping
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina. Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Wechsler-Reya
authors.affiliation: Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida. duane.mitchell@neurosurgery.ufl.edu.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D004195:Disease Models, Animal; D016130:Immunophenotyping; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D000072079:Patched Receptors; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface