Skip to main content

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

Publication ,  Journal Article
Pham, CD; Flores, C; Yang, C; Pinheiro, EM; Yearley, JH; Sayour, EJ; Pei, Y; Moore, C; McLendon, RE; Huang, J; Sampson, JH; Wechsler-Reya, R ...
Published in: Clin Cancer Res
February 1, 2016

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

February 1, 2016

Volume

22

Issue

3

Start / End Page

582 / 595

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocyte Subsets
  • Receptors, Cell Surface
  • Programmed Cell Death 1 Receptor
  • Phenotype
  • Patched Receptors
  • Oncology & Carcinogenesis
  • Myeloid Cells
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Pham, C. D., Flores, C., Yang, C., Pinheiro, E. M., Yearley, J. H., Sayour, E. J., … Mitchell, D. A. (2016). Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma. Clin Cancer Res, 22(3), 582–595. https://doi.org/10.1158/1078-0432.CCR-15-0713
Pham, Christina D., Catherine Flores, Changlin Yang, Elaine M. Pinheiro, Jennifer H. Yearley, Elias J. Sayour, Yanxin Pei, et al. “Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.Clin Cancer Res 22, no. 3 (February 1, 2016): 582–95. https://doi.org/10.1158/1078-0432.CCR-15-0713.
Pham CD, Flores C, Yang C, Pinheiro EM, Yearley JH, Sayour EJ, et al. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma. Clin Cancer Res. 2016 Feb 1;22(3):582–95.
Pham, Christina D., et al. “Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.Clin Cancer Res, vol. 22, no. 3, Feb. 2016, pp. 582–95. Pubmed, doi:10.1158/1078-0432.CCR-15-0713.
Pham CD, Flores C, Yang C, Pinheiro EM, Yearley JH, Sayour EJ, Pei Y, Moore C, McLendon RE, Huang J, Sampson JH, Wechsler-Reya R, Mitchell DA. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma. Clin Cancer Res. 2016 Feb 1;22(3):582–595.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

February 1, 2016

Volume

22

Issue

3

Start / End Page

582 / 595

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocyte Subsets
  • Receptors, Cell Surface
  • Programmed Cell Death 1 Receptor
  • Phenotype
  • Patched Receptors
  • Oncology & Carcinogenesis
  • Myeloid Cells
  • Mice, Knockout
  • Mice