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Glioma MHC class II

Sadashib Ghosh, Piyushi Gupta, Ellora Sen
Hypoxia-inducible Factor-1α (HIF-1α)-regulated expression of Hexokinase-II (HKII) remains a cornerstone in the maintenance of high metabolic demands subserving various pro-tumor functions including immune evasion in gliomas. Since inflammation-induced HIF-1α regulates Major Histocompatibility Complex class I (MHC-I) gene expression, and as cytoskeletal dynamics affect MHC-I membrane clusters, we investigated the involvement of HIF-1α-HKII axis in Tumor Necrosis Factor-α (TNFα)-mediated MHC-I membrane cluster stability in glioma cells and the involvement of actin cytoskeleton in the process...
January 1, 2016: Experimental Cell Research
Theresa Schumacher, Lukas Bunse, Wolfgang Wick, Michael Platten
The discovery of driver mutations in cancers has raised interest in their suitability as immunotherapeutic targets. A recent study demonstrates that a point mutation in isocitrate dehydrogenase 1 (IDH1R132H), expressed in gliomas and other tumors, is presented on human MHC class II and induces a mutation-specific CD4(+) antitumor T cell response in patients and a syngeneic tumor model in MHC-humanized mice.
December 2014: Oncoimmunology
Lina Wang, Bo Wei, Guozhang Hu, Le Wang, Miaomiao Bi, Zhigang Sun, Ying Jin
Glioblastoma multiforme (GBM) is the most malignant type of human glioma, and has a poor prognosis. Screening differentially expressed genes (DEGs) in brain tumor samples and normal brain samples is of importance for identifying GBM and to design specific-targeting drugs. The transcriptional profile of GSE30563, containing three genechips of brain tumor samples and three genechips of normal brain samples, was downloaded from Gene Expression Omnibus to identify the DEGs. The differences in the expression of the DEGs in the two different samples were compared through hierarchical biclustering...
August 2015: Molecular Medicine Reports
Lukas Bunse, Theresa Schumacher, Felix Sahm, Stefan Pusch, Iris Oezen, Katharina Rauschenbach, Marina Gonzalez, Gergely Solecki, Matthias Osswald, David Capper, Benedikt Wiestler, Frank Winkler, Christel Herold-Mende, Andreas von Deimling, Wolfgang Wick, Michael Platten
For a targeted cancer vaccine to be effective, the antigen of interest needs to be naturally processed and presented on MHC by the target cell or an antigen-presenting cell (APC) in the tumor stroma. The presence of these characteristics is often assumed based on animal models, evaluation of antigen-overexpressing APCs in vitro, or assays of material-consuming immune precipitation from fresh solid tissue. Here, we evaluated the use of an alternative approach that uses the proximity ligation assay (PLA) to identify the presentation of an MHC class II-restricted antigen in paraffin-embedded tissue sections from patients with brain tumors...
February 2015: Journal of Clinical Investigation
Salina Ströjby, Sofia Eberstål, Andreas Svensson, Sara Fritzell, Daniel Bexell, Peter Siesjö, Anna Darabi, Johan Bengzon
Bone marrow-derived mesenchymal stromal cells (MSCs) target glioma extensions and micro-satellites efficiently when implanted intratumorally. Here, we report that intratumoral implantation of MSCs and peripheral immunotherapy with interferon-gamma (IFNγ) producing tumor cells improve the survival of glioma-bearing rats (54% cure rate) compared to MSC alone (0% cure rate) or immunotherapy alone (21% cure rate) by enforcing an intratumoral CD8(+) T cell response. Further analysis revealed that the MSCs up-regulate MHC classes I and II in response to IFNγ treatment in vitro and secrete low amounts of immunosuppressive molecules prostaglandin E2 and interleukin-10...
September 15, 2014: Journal of Neuroimmunology
Theresa Schumacher, Lukas Bunse, Stefan Pusch, Felix Sahm, Benedikt Wiestler, Jasmin Quandt, Oliver Menn, Matthias Osswald, Iris Oezen, Martina Ott, Melanie Keil, Jörg Balß, Katharina Rauschenbach, Agnieszka K Grabowska, Isabel Vogler, Jan Diekmann, Nico Trautwein, Stefan B Eichmüller, Jürgen Okun, Stefan Stevanović, Angelika B Riemer, Ugur Sahin, Manuel A Friese, Philipp Beckhove, Andreas von Deimling, Wolfgang Wick, Michael Platten
Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref...
August 21, 2014: Nature
Audrey Bouchet, Nathalie Sakakini, Michèle El Atifi, Céline Le Clec'h, Elke Brauer, Anaïck Moisan, Pierre Deman, Pascal Rihet, Géraldine Le Duc, Laurent Pelletier
Synchrotron Microbeam Radiation Therapy (MRT) relies on the spatial fractionation of the synchrotron photon beam into parallel micro-beams applying several hundred of grays in their paths. Several works have reported the therapeutic interest of the radiotherapy modality at preclinical level, but biological mechanisms responsible for the described efficacy are not fully understood to date. The aim of this study was to identify the early transcriptomic responses of normal brain and glioma tissue in rats after MRT irradiation (400Gy)...
2013: PloS One
Michael J Ciesielski, Manmeet S Ahluwalia, Stephan A Munich, Molly Orton, Tara Barone, Asher Chanan-Khan, Robert A Fenstermaker
Survivin is a tumor-associated antigen with significant potential as a cancer vaccine target. We have identified a survivin peptide mimic containing human MHC class I epitopes and a potential class II ligand that induces a potent antitumor response in C57BL/6 mice with GL261 cerebral gliomas. This peptide is able to elicit both CD8+ CTL and T helper cell responses in C57BL/6 mice. The corresponding region of the human survivin molecule represented by peptide SVN53-67 is 100% homologous to the murine protein, but SVN53-67 is weakly immunogenic in man...
August 2010: Cancer Immunology, Immunotherapy: CII
Christian Ginzkey, Sven O Eicker, Matthias Marget, Joerg Krause, Stephan Brecht, Manfred Westphal, Hans H Hugo, H M Mehdorn, Joerg Steinmann, Wolfgang Hamel
The immunosuppressive environment of malignant gliomas is likely to suppress the anti-tumor activity of infiltrating microglial cells and lymphocytes. Macrophages and microglial cells may be activated by oligonucleotides containing unmethylated CpG-motifs, although their value in cancer immunotherapy has remained controversial. Following injection of CpG-containing oligonucleotides (ODN) into normal rat brain, we observed a local inflammatory response with CD8+ T cell infiltration, upregulation of MHC 2, and ED1 expression proving the immunogenic capacity of the CpG-ODN used...
April 2010: Cancer Immunology, Immunotherapy: CII
Der-Yang Cho, Shinn-Zong Lin, Wen-Kuang Yang, Den-Mei Hsu, Han-Chung Lee, Wen-Yeun Lee, Shih-Ping Liu
Immunotherapy is a new light of hope for the treatment of malignant gliomas. The brain is no longer believed to be an immunologically privileged organ. The major advantage of immunotherapy is the tumor-specific cytotoxic effect on the tumor cells with minimal side effects. Autologous dendritic cells (DCs)-based immunotherapy is a promising and feasible method. DCs are the most potent antigen-presenting cells (APCs). DCs prime T lymphocytes by epitopic major histocompatibility (MHC) class I and II for CD8(+) cytotoxic T lymphocytes (CTLs) and CD4(+) T helper cells, respectively...
2009: Cell Transplantation
Natalie Kronik, Yuri Kogan, Vladimir Vainstein, Zvia Agur
Glioblastoma (GBM), a highly aggressive (WHO grade IV) primary brain tumor, is refractory to traditional treatments, such as surgery, radiation or chemotherapy. This study aims at aiding in the design of more efficacious GBM therapies. We constructed a mathematical model for glioma and the immune system interactions, that may ensue upon direct intra-tumoral administration of ex vivo activated alloreactive cytotoxic-T-lymphocytes (aCTL). Our model encompasses considerations of the interactive dynamics of aCTL, tumor cells, major histocompatibility complex (MHC) class I and MHC class II molecules, as well as cytokines, such as TGF-beta and IFN-gamma, which dampen or increase the pro-inflammatory environment, respectively...
March 2008: Cancer Immunology, Immunotherapy: CII
Rolf K Swoboda, Rajasekharan Somasundaram, Laura Caputo, Elizabeth M Ochoa, Phyllis A Gimotty, Francesco M Marincola, Patricia Van Belle, Stephen Barth, David Elder, DuPont Guerry, Brian Czerniecki, Lynn Schuchter, Robert H Vonderheide, Dorothee Herlyn
Antigens recognized by T helper (Th) cells in the context of MHC class II molecules have vaccine potential against cancer and infectious agents. We have described previously a melanoma patient's HLA-DR7-restricted Th cell clone recognizing an antigen, which is shared among melanoma and glioma cells derived from various patients. Here, this antigen was cloned using a novel antigen phage display approach. The antigen was identified as the ribosomal protein L8 (RPL8). A peptide of RPL8 significantly stimulated proliferation and/or cytokine expression of the Th cell clone and lymphocytes in four of nine HLA-DR7(+) melanoma patients but not in healthy volunteers...
April 15, 2007: Cancer Research
Takayuki Amano, Koji Kajiwara, Koichi Yoshikawa, Jun Morioka, Sadahiro Nomura, Hirosuke Fujisawa, Shoichi Kato, Masami Fujii, Mikiko Fukui, Yuji Hinoda, Michiyasu Suzuki
OBJECT: The receptor for hyaluronan-mediated motility (RHAMM) is frequently overexpressed in brain tumors and was recently identified as an immunogenic antigen by using serological screening of cDNA expression libraries. In this study, which was conducted using a mouse glioma model, the authors tested the hypothesis that vaccination with dendritic cells transfected with RHAMM mRNA induces strong immunological antitumor effects. METHODS: The authors constructed a plasmid for transduction of the mRNAs transcribed in vitro into dendritic cells, which were then used to transport the intracellular protein RHAMM efficiently into major histocompatibility complex class II compartments by adding a late endosomal-lysosomal sorting signal to the RHAMM gene...
April 2007: Journal of Neurosurgery
Fatemeh Geranmayeh, Bernd W Scheithauer, Christoph Spitzer, Fredric B Meyer, Ann-Cathrin Svensson-Engwall, Manuel B Graeber
OBJECTIVE: Although gemistocytic astrocytomas are graded as World Health Organization II astrocytomas, they behave more aggressively than other astrocytomas. Their proliferative potential is low, and it remains an intriguing question why these tumors are so biologically "successful." They show a high mutation rate of the P53 gene, cytological abnormalities, and frequent perivascular mononuclear infiltrates. Microglial cells, a feature of this astrocytoma variant, are of increasing interest in the context of glioma growth...
January 2007: Neurosurgery
Oliver Grauer, Peter Pöschl, Annette Lohmeier, Gosse J Adema, Ulrich Bogdahn
Malignant gliomas are able to secrete large amounts of immunosuppressive cytokines like transforming growth factor beta 2 (TGF-beta2) and regularly escape from immune surveillance. Many strategies have been developed to induce potent anti-glioma responses, among those the use of dendritic cells (DC) as therapeutic vaccines. Here, we report that both mature DC and IL-12 secretion are necessary to overcome T-cell inhibition by TGF-beta2. Flow cytometric analyses showed that TGF-beta2 does not suppress the upregulation of MHC (major histocompatibility complex) class II molecules and the T cell stimulatory capacity of human DC that were stimulated with a strong cytokine cocktail containing tumor necrosis factor alpha (TNF-alpha), IL-1beta, IL-6 and prostaglandin E2 (PGE2)...
April 2007: Journal of Neuro-oncology
Karin E Smith, Shorena Janelidze, Edward Visse, Wiaam Badn, Leif Salford, Peter Siesjö, Anna Darabi
Glioblastoma multiforme is the most common malignant primary brain tumor and also one of the most therapy-resistant tumors. Because of the dismal prognosis, various therapies modulating the immune system have been developed in experimental models. Previously, we have shown a 37-70% cure in a rat glioma model where rats were peripherally immunized with tumor cells producing IFNgamma. On the basis of these results, we wanted to investigate whether a combination of GM-CSF and IFNgamma could improve the therapeutic effect in a mouse glioma model, GL261 (GL-wt)...
January 1, 2007: International Journal of Cancer. Journal International du Cancer
Günter Eisele, Jörg Wischhusen, Michel Mittelbronn, Richard Meyermann, Inja Waldhauer, Alexander Steinle, Michael Weller, Manuel A Friese
NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They transmit danger signals to NKG2D-expressing immune cells, leading to lysis of NKG2DL-expressing cells. We here report that the NKG2DL MHC class I-chain-related molecules A and B (MICA/B) and UL16-binding proteins (ULBP) 1-3 are expressed in human brain tumours in vivo, while expression levels are low or undetectable in normal brain. MICA and ULBP2 expression decrease with increasing WHO grade of malignancy, while MICB and ULBP1 are expressed independently of tumour grade...
September 2006: Brain: a Journal of Neurology
Jill M Schartner, Aaron R Hagar, Michelle Van Handel, Leying Zhang, Nivedita Nadkarni, Behnam Badie
Immunotherapy for malignant gliomas is being studied as a possible adjunctive therapy for this highly fatal disease. Thus far, inadequate understanding of brain tumor immunology has hindered the design of such therapies. For instance, the role of microglia and macrophages, which comprise a significant proportion of tumor-infiltrating inflammatory cells, in the regulation of the local anti-tumor immune response is poorly understood. To study the response of microglia and macrophages to known activators in brain tumors, we injected CpG oligodeoxynucleotide (ODN), interferon-gamma (IFN-gamma), and IFN-gamma/LPS into normal and intracranial RG2 glioma-bearing rodents...
September 2005: Glia
David Zagzag, Konstantin Salnikow, Luis Chiriboga, Herman Yee, Li Lan, M Aktar Ali, Roberto Garcia, Sandra Demaria, Elizabeth W Newcomb
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 technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection...
March 2005: Laboratory Investigation; a Journal of Technical Methods and Pathology
Steven De Vleeschouwer, Mohammed Arredouani, Martine Adé, Pascal Cadot, Elke Vermassen, Jan L Ceuppens, Stefaan W Van Gool
Malignant glioma of the CNS is a tumor with a very bad prognosis. Development of adjuvant immunotherapy is hampered by interindividual and intratumoral antigenic heterogeneity of gliomas. To evaluate feasibility of tumor vaccination with (autologous) tumor cells, we have studied uptake of tumor cell lysates by dendritic cells (DCs), and the T-cell stimulatory capacity of the loaded DCs. DCs are professional antigen-presenting cells, which have already been used as natural adjuvants to initiate immune responses in human cancer...
April 2005: Cancer Immunology, Immunotherapy: CII
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