Cytokines and immunoregulatory molecules in malignant glial neoplasms

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✓ Cytokines are important regulatory proteins controlling growth and differentiation of normal and malignant glial cells. Astrocytes and microglial cells produce and respond to many of the same cytokines employed by cells of the immune system. The authors have analyzed 15 histologically confirmed malignant glial neoplasms for the presence of infiltrating lymphocytes, macrophages, cytokines, and other immunoregulatory molecules using a panel of specific monoclonal and polyclonal antibodies on frozen-tissue sections. All neoplasms showed focal T-cell infiltration with CD8 cells predominating. Infiltration of activated macrophages (positive for CD11c, class II, and interleukin-2 receptor) was marked in all tumors. Within the neoplasm, tumor necrosis factor-α (TNF-α)- and interleukin (IL)-6-positive macrophages were prominent in five cases, while the tumor cells themselves were only weakly positive. In the other 10 cases, the numerous infiltrating macrophages were only rarely immunoreactive for TNF-α or IL-6. Transforming growth factor-β (TGF-β) immunoreactivity was most prominent in those tumors with little TNF-α-positive macrophage infiltration, although intratumoral variability was present. This study suggests that, in malignant gliomas, the cytokines TNF-α and IL-6, although weakly present in neoplastic cells, are most prominent in infiltrating macrophages and in those regions of the tumors that show little immunoreactivity for TGF-β. The important interactions among neoplastic, reactive glial, and inflammatory cells, which regulate tumor growth, are likely to be in part mediated through these molecules.

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Address reprint requests to: David R. Hinton, M.D., Department of Pathology, University of Southern California School of Medicine, 2011 Zonal Avenue, HMR 204, Los Angeles, California 90033.

© AANS, except where prohibited by US copyright law.

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Figures

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    Photomicrographs showing histological features of three glioblastomas multiforme studied. Paraffin tissue sections. H & E. A to C: Sections from the neoplasm in Case 1, showing a hypercellular tumor with necrosis (n) (A, × 63), prominent vascular proliferation (B, × 63). and occasional mitotic (arrow) figures (C, × 250). All of the other tumors showed similar features, however the vascular proliferation was most prominent in Case 1. D: Representative sections of the tumor in Case 2. × 250. E: Section from the tumor in Case 3 showing mitotic figures (arrows), × 250.

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    Photomicrographs showing interleukin-2 (IL-2) and IL-2-receptor localization in representative glioblastomas multiforme. All tumors showed occasional infiltrating lymphocytes with an overall predominance of CD8 cells. H & E. A: Only occasional CD8 cells infiltrated the tumor parenchyma (arrowheads). × 250. B: Very rare perivascular lymphocytes showed immunoreactivity for IL-2 (arrows). × 500. C and D: The immunoreactivity of IL-2 receptor was prominent on a subset of morphologically identified macrophages. All cases were positive for this feature, but representative cells from Cases 1 (C) and 3 (D) are shown, × 500.

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    Photomicrographs demonstrating reactivity of glioblastoma multiforme tissue to cytokines and immunoregulatory molecules. Immunoperoxidase staining of sections from Case 1 (columns 1 and 2), Case 2 (column 3), and Case 3 (column 4) with antibodies reactive with CD11c (row 1), HLA-DR (row 2), tumor necrosis factor (TNF)-α (row 3), interleukin-6 (IL-6) (row 4), and transforming growth factor (TGF)-β (row 5). All cases showed prominent macrophage (CD11c-positive) infiltration which was both perivascular (arrow) (A, × 50) and intraparenchymal (D, × 200). Morphology of the macrophages at higher magnification is shown (B and C, × 500). The macrophages were strongly positive for class II antigens (HLA-Dr), while the tumor cells were weakly positive. In Case 1, the blood vessel (v) is surrounded by numerous positive macrophages (E, × 50; F, × 200). In Case 2 (G, × 500), a single strong positive macrophage is identified with only weakly or negatively stained endothelial cells. In Case 3 (H, × 500), the negative-staining vessel (v) walls stand out in comparison with the strongly positive macrophages. In Case 1, numerous cells (arrowheads) strongly positive for TNF-α were identified (I, × 200), while the tumor cells showed weak diffuse reactivity. At higher magnification, the strongly positive cells were morphologically identified as macrophages (J and K, × 500). The Case 3 tumor did not have any infiltrating macrophages positive for TNF-α, but the tumor cells were very weakly positive (L, × 200). In Cases 1 and 2, there was strong positivity for IL-6 (M, × 50). At higher magnification the IL-6-positive cells were identified as macrophages (N and O, × 500). Case 3 had only weak diffuse tumor cells reactive for IL-6 (P, × 50). The Case 1 tumor showed only focal perinuclear reactivity for TGF-β (Q, × 50), indicated by arrowheads at higher magnification (R, × 500). In Case 2, the tumor also showed very weak but more diffuse reactivity (S, × 500). The specimen from Case 3 showed strong diffuse reactivity for TGF-β (T, × 200; inset, × 500).

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