The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1
Departments of Neurosurgery (S.F.H., D.Y., D.S., A.B.H.), Neuropathology (K.A.), and Experimental Therapeutics (E.G.), The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230, USA
2 Address correspondence and requests for reprints to Amy B. Heimberger, Department of Neurosurgery, Unit 442, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, USA (aheimber{at}mdanderson.org).
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Abstract |
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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 
, 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.
Keywords: costimulation, human glioma, macrophages, microglia, regulatory T cells, tumor immunotherapy
Received August 24, 2005; Accepted March 30, 2006
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