In vitro Prostaglandin E2 production by glioblastoma cells and its effect on interleukin-2 activation of oncolytic lymphocytes

Sawamura, Yutaka; Diserens, A.-C.; Tribolet, Nicolas de

doi:10.1007/bf02427832

Cited by 67 publications

(28 citation statements)

References 23 publications

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“…Glioma-mediated immunosuppression and downregulation of the host immune response has been associated with the release of immunosuppressive factors by glioma cells, for example, transforming growth factor (TGF)-b1, b2, and b3. [32][33][34][35][36][37][38] In addition to TGF-b, other factors capable of inhibiting immune function 37 include the cytokines interleukin (IL)-6 and IL-10, [39][40][41][42][43][44][45] prostaglandin E, [46][47][48][49][50] and gangliosides. 51 TGF-b1 and IL-10 act by suppressing T cell function.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Zagzag

Salnikow

Chiriboga

et al. 2005

Laboratory Investigation

156

105

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Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechip s technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex (MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo. Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT-PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for b2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo, respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a 'stealth'-like manner.

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Section: Discussionmentioning

confidence: 99%

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Zagzag

Salnikow

Chiriboga

et al. 2005

Laboratory Investigation

156

105

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“…Moreover, immunosuppressive surface molecules like Fas ligand or HLA-G have been identified in gliomas. [17][18][19][20][21] One of the most potent immunosuppressive effects are mediated by CD41CD251 regulatory T cells (Treg). They have the ability to suppress both the proliferation and effector functions of immune cells.…”

Section: -15mentioning

confidence: 99%

Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate‐pulsed dendritic cells in a murine glioma model

Grauer

Sutmuller

Maren

et al. 2007

Intl Journal of Cancer

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Both melanoma and glioma cells are of neuroectodermal origin and share common tumor associated antigens. In this article, we report that the melanocyte differentiation antigen TRP2 (tyrosinase-related protein 2) is not predominately involved in the tumor rejection of a syngeneic murine glioma. Although GL261 glioma cells endogenously expressed TRP2 and were lysed by TRP2 specific cytotoxic T cells (CTLs) in vitro, vaccinations with TRP2 peptide-pulsed dendritic cells (DCs) could only induce minor antiglioma responses in a prophylactic setting and failed to work in a stringent setting where vaccine and tumor were administered on the same day. Further analysis revealed that TRP2 is not recognized by bulk CTLs after depletion of regulatory T cells which results in tumor rejections in vivo. In contrast to TRP2 peptidepulsed DC, tumor lysate-pulsed DCs were more potent as a vaccine and completely protected mice from tumor outgrowth in a prophylactic setting. However, the vaccine efficacy of tumor lysate-pulsed DC was not sufficient to prevent the tumor outgrowth when tumors were inoculated the same day. In this case, Treg depletion before vaccination was essential to boost antiglioma immune responses leading to the rejection of 80% of the mice and long-term immunity. Therefore, we conclude that counteracting the immunosuppressive glioma tumor environment via depletion of regulatory T cells is a prerequisite for successful eradication of gliomas after targeting multiple tumor antigens by using tumor lysate-pulsed DCs as a vaccine in a more stringent setting. ' 2007 Wiley-Liss, Inc.Key words: glioma; TRP2; tumor lysate; dendritic cell; regulatory T cell; CD25-depletion Dendritic cell (DC)-based immunotherapy is regarded as an attractive strategy for the therapy of malignant gliomas. Several animal studies have demonstrated that DCs can efficiently mediate the induction of antitumor responses within the central nervous system. 1-9 A number of phase I/II studies have been performed and others are ongoing to evaluate and improve DC vaccines for patients with malignant gliomas. 10-15Although DC-based immunotherapies for various cancers including malignant gliomas led to the induction of antitumor cytotoxic T cells (CTLs) and lymphocyte infiltration into tumors in situ, objective tumor regressions have been limited to a few cases. 16 In addition, most mouse glioma models primarily assessed the ability of DC-based immunotherapy to prevent the outgrowth of tumor in a prophylactic setting in which tumor cells are injected after vaccination. Attempts to treat tumors at more stringent conditions, like administration of tumor cells and vaccine on the same day (simultaneous setting) or a therapeutic setting were either not evaluated or shown to be unsuccessful, despite the presence of large numbers of antiglioma immune cells.A major obstacle for an active immunization against solid tumors is the presence of immunosuppressive factors at the local tumor environment. There is accumulating evidence that active suppressor mechanisms ar...

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“…It has also been recently reported that IL-1, IL-6 and neutrophils also possess anticancer activity in animal models in vivo [25,28,34]. Inversely, TNFo~ raised the levels of PGE2 and TGF[~, which have been known to be produced by human glioblastoma cells and act as potential immunosuppressants [41,56].…”

Section: Discussionmentioning

confidence: 95%

Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas

Tada¹,

Sawamura²,

Sakuma³

et al. 1993

Cancer Immunol Immunother

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To elucidate the role of tumor necrosis factor alpha (TNF alpha) as a biological response modifier, we studied cellular and cytokine responses of the central nervous system to TNF alpha administered intracranially in a phase I clinical trial for patients with malignant gliomas. Six patients received injections of TNF alpha (1.25 x 10(3)-10 x 10(3) U/injection) into the tumor cavities, and regional fluids (RF) and lumbar cerebrospinal fluids (CF) were serially sampled before and after the injections. Recruitment of neutrophils occurred, mostly peaking 8 h after TNF alpha injection, and fewer numbers of CD4+ T cells and monocytes/macrophages migrated, subsequently peaking at 24 h. The CF leukocytosis persisted for 48 h and was associated with an increased level of neutrophil chemotactic activity in the CF. This neutrophil chemotactic activity was attributed to interleukin-8 (IL-8) by HPLC. The level of IL-6 activity in the CF and RF consistently increased; beginning 2 h after TNF alpha injection and reaching the maximum between 8 h and 12 h. It returned to the basal level within 48 h. IL-1 beta was detected in the CF of three patients, its level peaking at 8 h. Prostaglandin E2 also increased after injection of TNF alpha, peaking between 4 h and 12 h and then gradually decreasing. Transforming growth factor beta was found in all cases tested and one patient showed a significant change after TNF alpha injection. IL-2 activity, interferon alpha (INF alpha) activity, IFN beta, and granulocyte/macrophage-colony-stimulating factor were not detected in the CF or RF. In conclusion, TNF alpha is biologically effective in inducing migration of immune cells and generating multiple cytokine responses in the human central nervous system.

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In vitro Prostaglandin E2 production by glioblastoma cells and its effect on interleukin-2 activation of oncolytic lymphocytes

Cited by 67 publications

References 23 publications

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate‐pulsed dendritic cells in a murine glioma model

Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas

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