Systemic immune suppression in glioblastoma

The interplay between CD14 +HLA-DR lo/neg monocytes, tumor factors, and dexamethasone

Michael Gustafson, Yi Lin, Kent C. New, Peggy A. Bulur, Brian Patrick O'Neill, Dennis A. Gastineau, Allan B Dietz

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better nderstanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood and compared these to normal donors. In doing so, we identified changes in systemic immunity associated with both the tumor and dexamethasone treated tumor bearing patients. In particular, dexamethasone exacerbated tumor associated lymphopenia primarily in the T cell compartment. We have also identified unique tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes CD14 +HLA- DR lo/neg) had a phenotype distinct from classical myeloid suppressor cells. These cells inhibited T cell proliferation, were unable to fully differentiate into mature dendritic cells, were associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. We provide evidence that tumors express high levels of CCL2, can contain high numbers of CD141 cells, that tumor supernatants can transform CD14 +HLA-DR + cells into CD14 +HLA- DR lo/neg immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD141 cells.

Original languageEnglish (US)
Pages (from-to)631-644
Number of pages14
JournalNeuro-Oncology
Volume12
Issue number7
DOIs
StatePublished - Jul 2010

Fingerprint

HLA-DR Antigens
Glioblastoma
Dexamethasone
Monocytes
Neoplasms
T-Lymphocytes
Phenotype
Lymphopenia
Myeloid Cells
Therapeutics
Dendritic Cells
Immunity
Cell Count
Cell Proliferation
Tissue Donors

Keywords

  • Dexamethasone
  • Glioblastoma
  • Immune suppression
  • Monocytes
  • Myeloid suppressor cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Systemic immune suppression in glioblastoma : The interplay between CD14 +HLA-DR lo/neg monocytes, tumor factors, and dexamethasone. / Gustafson, Michael; Lin, Yi; New, Kent C.; Bulur, Peggy A.; O'Neill, Brian Patrick; Gastineau, Dennis A.; Dietz, Allan B.

In: Neuro-Oncology, Vol. 12, No. 7, 07.2010, p. 631-644.

Research output: Contribution to journalArticle

@article{98d1ee47369e4e3cb09cd9ad8f3c2bfd,
title = "Systemic immune suppression in glioblastoma: The interplay between CD14 +HLA-DR lo/neg monocytes, tumor factors, and dexamethasone",
abstract = "Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better nderstanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood and compared these to normal donors. In doing so, we identified changes in systemic immunity associated with both the tumor and dexamethasone treated tumor bearing patients. In particular, dexamethasone exacerbated tumor associated lymphopenia primarily in the T cell compartment. We have also identified unique tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes CD14 +HLA- DR lo/neg) had a phenotype distinct from classical myeloid suppressor cells. These cells inhibited T cell proliferation, were unable to fully differentiate into mature dendritic cells, were associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. We provide evidence that tumors express high levels of CCL2, can contain high numbers of CD141 cells, that tumor supernatants can transform CD14 +HLA-DR + cells into CD14 +HLA- DR lo/neg immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD141 cells.",
keywords = "Dexamethasone, Glioblastoma, Immune suppression, Monocytes, Myeloid suppressor cells",
author = "Michael Gustafson and Yi Lin and New, {Kent C.} and Bulur, {Peggy A.} and O'Neill, {Brian Patrick} and Gastineau, {Dennis A.} and Dietz, {Allan B}",
year = "2010",
month = "7",
doi = "10.1093/neuonc/noq001",
language = "English (US)",
volume = "12",
pages = "631--644",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Systemic immune suppression in glioblastoma

T2 - The interplay between CD14 +HLA-DR lo/neg monocytes, tumor factors, and dexamethasone

AU - Gustafson, Michael

AU - Lin, Yi

AU - New, Kent C.

AU - Bulur, Peggy A.

AU - O'Neill, Brian Patrick

AU - Gastineau, Dennis A.

AU - Dietz, Allan B

PY - 2010/7

Y1 - 2010/7

N2 - Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better nderstanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood and compared these to normal donors. In doing so, we identified changes in systemic immunity associated with both the tumor and dexamethasone treated tumor bearing patients. In particular, dexamethasone exacerbated tumor associated lymphopenia primarily in the T cell compartment. We have also identified unique tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes CD14 +HLA- DR lo/neg) had a phenotype distinct from classical myeloid suppressor cells. These cells inhibited T cell proliferation, were unable to fully differentiate into mature dendritic cells, were associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. We provide evidence that tumors express high levels of CCL2, can contain high numbers of CD141 cells, that tumor supernatants can transform CD14 +HLA-DR + cells into CD14 +HLA- DR lo/neg immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD141 cells.

AB - Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better nderstanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood and compared these to normal donors. In doing so, we identified changes in systemic immunity associated with both the tumor and dexamethasone treated tumor bearing patients. In particular, dexamethasone exacerbated tumor associated lymphopenia primarily in the T cell compartment. We have also identified unique tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes CD14 +HLA- DR lo/neg) had a phenotype distinct from classical myeloid suppressor cells. These cells inhibited T cell proliferation, were unable to fully differentiate into mature dendritic cells, were associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. We provide evidence that tumors express high levels of CCL2, can contain high numbers of CD141 cells, that tumor supernatants can transform CD14 +HLA-DR + cells into CD14 +HLA- DR lo/neg immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD141 cells.

KW - Dexamethasone

KW - Glioblastoma

KW - Immune suppression

KW - Monocytes

KW - Myeloid suppressor cells

UR - http://www.scopus.com/inward/record.url?scp=78349293679&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78349293679&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noq001

DO - 10.1093/neuonc/noq001

M3 - Article

VL - 12

SP - 631

EP - 644

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 7

ER -