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Clin Cancer Res. 2016 Feb 1;22(3):582-95. doi: 10.1158/1078-0432.CCR-15-0713. Epub 2015 Sep 24.

Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

Author information

1
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.
2
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.
3
Merck & Co., Inc., Kenilworth, New Jersey.
4
Cancer and Immunology Department, Brain Tumor Institute, Children's National Medical Center, Washington, District of Columbia.
5
Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, California.
6
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
7
Department of Pathology, Duke University Medical Center, Durham, North Carolina. Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
8
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.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN AND 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.

PMID:
26405194
PMCID:
PMC4922139
DOI:
10.1158/1078-0432.CCR-15-0713
[Indexed for MEDLINE]
Free PMC Article

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