The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses.
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.
Hussain
S Farzana
SF
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, USA.
Yang
David
D
Suki
Dima
D
Aldape
Kenneth
K
Grimm
Elizabeth
E
Heimberger
Amy B
AB
D000912:Antibodies, Neoplasm / Q000096:biosynthesis* / Q000502:physiology; D000921:Antibody-Producing Cells / Q000276:immunology / Q000473:pathology; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D005910:Glioma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009361:Neoplasm Invasiveness
D000912:Antibodies, Neoplasm; D014408:Biomarkers, Tumor