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

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2006-07, Vol.8 (3), p.261-279
• Main Authors: Hussain, S Farzana, Yang, David, Suki, Dima, Aldape, Kenneth, Grimm, Elizabeth, Heimberger, Amy B
• Format: Article
• Language: English
• Subjects: Antibodies, Neoplasm - biosynthesis; Antibodies, Neoplasm - physiology; Antibody-Producing Cells - immunology; Antibody-Producing Cells - pathology; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - pathology; Biomarkers, Tumor - immunology; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Glioma - immunology; Glioma - pathology; Humans; Macrophages - immunology; Macrophages - pathology; Microglia - immunology; Microglia - pathology; Neoplasm Invasiveness
• ISSN: 1522-8517
• DOI: 10.1215/15228517-2006-008

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 ( approximately 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 alpha, 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.