The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses

S. Farzana Hussain, David Yang, Dima Suki, Kenneth Aldape, Elizabeth Grimm, Amy B. Heimberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

388 Scopus citations

Abstract

Little is known about the immune performance and interactions of CNS microglia/macrophages in glioma patients. We found that microglia/macrophages were the predominant immune cell infiltrating gliomas (∼1% of total cells); others identified were myeloid dendritic cells (DCs), plasmacytoid DCs, and T cells. We isolated and analyzed the immune functions of CD11b/C+CD45+ glioma-infiltrating microglia/macrophages (GIMs) from postoperative tissue specimens of glioma patients. Although GIMs expressed substantial levels of Toll-like receptors (TLRs), they did not appear stimulated to produce pro-inflammatory cytokines (tumor necrosis factor a, interleukin 1, or interleukin 6), and in vitro, lipopolysaccharides could bind TLR-4 but could not induce GIM-mediated T-cell proliferation. Despite surface major histocompatibility complex class II expression, they lacked expression of the costimulatory molecules CD86, CD80, and CD40 critical for T-cell activation. Ex vivo, we demonstrate a corresponding lack of effector/activated T cells, as glioma-infiltrating CD8+ T cells were phenotypically CD8+CD25-. By contrast, there was a prominent population of regulatory CD4 T cells (CD4+CD25+FOXP3+) infiltrating the tumor. We conclude that while GIMs may have a few intact innate immune functions, their capacity to be stimulated via TLRs, secrete cytokines, upregulate costimulatory molecules, and in turn activate antitumor effector T cells is not sufficient to initiate immune responses. Furthermore, the presence of regulatory T cells may also contribute to the lack of effective immune activation against malignant human gliomas.

Original languageEnglish (US)
Pages (from-to)261-279
Number of pages19
JournalNeuro-oncology
Volume8
Issue number3
DOIs
StatePublished - Jul 2006
Externally publishedYes

Keywords

  • Costimulation
  • Human glioma
  • Macrophages
  • Microglia
  • Regulatory T cells
  • Tumor immunotherapy

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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