Analysis of immunosuppressive states in patients with malignant glioma

1998 Fiscal Year Final Research Report Summary

• Project/Area Number: 09671414
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Yamanashi Medical University
• Principal Investigator: NAGANUMA Hirofumi Yamanashi Medical University, Department of Neurosurgery, Assosiate Professor, 医学部, 助教授 (90189142)
• Project Period (FY): 1997 – 1998
• Keywords: malignant glioma / transforming growth factor-beta / thrombospondin / immunosuppression

Research Abstract

In this study, we investigated to the mechanisms of immunosuppressive states in patients with malignant glioma.
1) The effect of IFN-beta on the expression of CD8O and CD86 molecules in peripheral blood monocytes was examined. IFN-beta modulated the expression of those molecules. However, the effect was different between in vitro and in vivo.
2) Presense of immunosuppressive IL-12 p40 homodimer was examined in the patients with malignant glioma. Relatively high levels of IL-12 p40 homodimer were present and bioactive p70 heterodimer was not detected in the patients. This suggests that presense of the IL-12 p40 homodimer may inhibit the initiation of immune reaction against glioma cells.
3) Production of TSP-1 by malignant glioma cells and role of TSP-1 in the latent TGF-beta activation were examined. All malignant glioma cell lines expressed TSP-1 mRNA and protein, and had the capacity of latent TGF-beta activation. The TGF-beta activation was inhibited by more than 50% by the addition of neutralizing anti-TSP-I antibodies. This suggests that TSP-1 predominantly participated in the TGF-beta activation in malignant glioma cells.
4) Correlation of TSP-1 expression with malignancy of gliomas was examined. A localization of TSP-i, TGF-beta was examined immunohistochemically in surgically resected glioma tissues. Most glioblastomas highly expressed both TSP-1 and TGF-beta. Anaplastic astrocytomas expressed moderate levels of TSP-i and TGF-beta, On the other hand, the expression of both proteins was weak in low grade gliomas. Normal brain tissues around the tumors were negative or very weakly positive for TSP-i and TGF-beta. The expression of TSP-i and TGF-beta in situ correlated with the histological malignancy of glioma.
These data indicate that the presense of the IL-12 p40 homodimer may relates to the immunosuppressive states of the patients and the overexpression of both TSP-i and TGF-beta may increase biological malignancy of malignant gliomas, through generating an active form of TGF-beta which may exert a local immunosuppression in tumor tissues. Biological significance of TSP-1 overexpression, especially its role on tumor cell invasion, in malignant glioma cells is needed to be further investigated.