Immunological considerations of modern animal models of malignant primary brain tumors (original) (raw)
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Immunocompetent murine models for the study of glioblastoma immunotherapy
Journal of Translational Medicine, 2014
Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.
Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma
Cancers, 2020
Simple Summary Glioblastoma (GBM) remains the most aggressive brain tumor. Treatment typically includes surgery and radio/chemotherapy, but in spite of intensive treatment, virtually all tumors recur within the time-frame of months with insufficient and unsuccessful second line options. This clinical reality is in contrast to preclinical animal experiments, which often show successful outcomes of novel immunotherapeutic approaches. This discrepancy is largely explained by the small number of animal models and their limited capacity to mimic the complexity of the human disease. Moreover, new treatment options are typically administered as single treatments in animal models, whereas patients receive them in combination with standard-of-care. In this review, we provide an overview of the existing mouse models for GBM research and how each of them mimic (parts of) the human disease spectrum. As such we provide an overview of the advantages and limitations of the currently available opti...
Immune landscape of a genetically engineered murine model of glioma compared with human glioma
JCI Insight
Data set. The scSeq data set has been deposited in the GEO database (GSE147275). Code. Code used to generate figures and analyze data is available at https://github.com/zamlerd/Single\_ Cell_Sequencing (commit ID 6dbce63). Experimental model and patient details Mouse models. The QPP spontaneous glioma model exists on a mixed background and is maintained in-house at the MD Anderson Cancer Center in the Department of Cancer Biology. Frozen sperm have also been deposited in the MD Anderson Mouse Transgenics Core. Patient data. Patient information, including sex, genomic information, and site of resection, etc., is available in Supplemental Table 1. Key resources Details regarding antibodies are provided in Supplemental Table 2. Biological samples, including patient tissue, were provided by the MD Anderson Cancer Center. Critical commercial assays included the Chromium Single Cell 3′ Reagent Kit (10x Genomics) and the ImmPACT NovaRED HRP substrate (Vector Laboratories). C57BL/6J mice were obtained from The Jackson Laboratory (strain 000664).
Investigation of immunosuppressive mechanisms in a mouse glioma model
Journal of Neuro-Oncology, 2009
The development of an immune competent mouse model for the study of immunosuppressive mechanisms is important for improving the efficacy of brain tumor immunotherapy. In the present study we investigated regulatory T cells (Tregs), TGF-b1 and other putative immunosuppressive cytokines using GL261 mouse glioma in C57BL mice. We explored whether tumor growth factor-beta1 (TGF-b1) is expressed and secreted by glioma cells constitutively or in response to a T-cell mediated immunity (simulated by conditioned media from T cells (TCM) activated by anti-CD3 antibody). We also investigated TGF-b1's role in Treg mediated immunosuppression by quantifying TGF-b1secretion from T regulatory cells (Tregs) co-incubated with GL261 cells as compared to Tregs alone. Finally, we studied other newly identified cytokines that were secreted preferentially by glioma cells in response to CD3 activated TCM versus cytokines secreted by glioma cells in absence of T-cell activation (naïve TCM). TGF-b1expression was studied using RT-PCR and secretion was quantified using ELISA. A 308 protein cytokine array was used to identify and quantify cytokine expression. TGF-b1expression and secretion from glioma cells was found to be up-regulated by conditioned media from CD3-activated T cells, suggesting that this immunosuppressive cytokine is not secreted constitutively but in response to immunity. TGF-b1 was not found to be differentially secreted by Tregs co-incubated with glioma cells as compared to Tregs alone. This data suggest that TGF-b1immunosupppression may not be a Treg dependent mechanism in this glioma model. Finally, the cytokine array elucidated several other cytokines which were upregulated or down-regulated by CD3-activated TCM. These results have several implications for enhancing immunotherapy treatment, including the potential benefit of TGF-b1inhibition in conjunction with immunotherapy, as well as the illumination of several other potential cytokine targets to be explored as shown by the cytokine array.
Frontiers in Oncology, 2021
High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.
Induction of human glioma tumor in sprague-dawley rat with intact immune system
Turkish Neurosurgery, 2016
it provides the possibility to investigate the histological and genetic characteristics of neoplasms (11). Commonly applied models that generate brain neoplasms in animals include: a) Chemical mutagen-induced models (36) b) Genetic modification-induced models (2) c) Xenograft induced models (20, 30). These models have led to better understanding of the mechanisms related to tumor progression. However, these models are not comprehensive, and each of the models has its own issues (18, 31). The major drawbacks of chemically induced brain tumors include their histological characteristics █ INTRODUCTION G lioblastoma (GBM) is a common and aggressive type of brain tumor in humans. Despite improvement in therapy techniques, patients have a short life expectancy (12-15 months) and GBM is an incurable disease (7, 32). The inefficacy of current treatment methods stimulates the researchers to seek novel therapeutic agents and strategies. So, development of laboratory and animal model is a substantial step for the advances in the treatment of GBM (19, 23). An animal model is an important tool for the understanding of complex phenomena involved in glioma generation; and AIm: Glioblastoma (GBM) is an aggressive brain tumor in humans. The median survival rate of patients is one year after the diagnosis. So, development of an animal model is necessary for the advances in the research treatment of GBM. The aim of this study was to investigate the capability of human glioma cells in inducing glioma tumors in rats with intact immune system. mATERIAl and mEThODS: U87 cells were implanted in the frontal lobe of rats without suppressing the immune system. We used magnetic resonance imaging (MRI), Hematoxylin-Eosin (H&E) and Immunohistochemical (IHC) staining to assess characteristics of tumor. RESUlTS: At the 10 th and 14 th days of tumor inoculation, MRI images contained the tumor areas in the brain. All tumor-bearing rats developed tumors. The rats retained the morphology and histological characteristics of human glioma. Animals mimic GBM characteristics, such as mitotic activity, invasion, neovascularization, necrosis and pseudopalisading cells. IHC staining revealed tumor growth and progression in the tumor-bearing rats. CONClUSION: This model is a standard system for studying the tumor phenotype, genotype, and for evaluating the efficacy of anti-cancer agents. It is a reliable, simple, inexpensive, and easily reproducible model, which may be a way for pre-clinical studies.
Immune microenvironment of gliomas
Laboratory Investigation, 2017
High-grade gliomas are rapidly progressing tumors of the central nervous system (CNS) with a very poor prognosis despite extensive resection combined with radiation and/or chemotherapy. Histopathological and flow cytometry analyses of human and rodent experimental gliomas revealed heterogeneity of a tumor and its niche, composed of reactive astrocytes, endothelial cells, and numerous immune cells. Infiltrating immune cells consist of CNS resident (microglia) and peripheral macrophages, granulocytes, myeloid-derived suppressor cells (MDSCs), and T lymphocytes. Intratumoral density of glioma-associated microglia/macrophages (GAMs) and MDSCs is the highest in malignant gliomas and inversely correlates with patient survival. Although GAMs have a few innate immune functions intact, their ability to be stimulated via TLRs, secrete cytokines, and upregulate co-stimulatory molecules is not sufficient to initiate antitumor immune responses. Moreover, tumor-reprogrammed GAMs release immunosuppressive cytokines and chemokines shaping antitumor responses. Both GAMs and MDSCs have ability to attract T regulatory lymphocytes to the tumor, but MDSCs inhibit cytotoxic responses mediated by natural killer cells, and block the activation of tumor-reactive CD4 + T helper cells and cytotoxic CD8 + T cells. The presence of regulatory T cells may further contribute to the lack of effective immune activation against malignant gliomas. We review the immunological aspects of glioma microenvironment, in particular composition and various roles of the immune cells infiltrating malignant human gliomas and experimental rodent gliomas. We describe tumor-derived signals and mechanisms driving myeloid cell accumulation and reprogramming. Although, understanding the complexity of cell-cell interactions in glioma microenvironment is far from being achieved, recent studies demonstrated several glioma-derived factors that trigger migration, accumulation, and reprogramming of immune cells. Identification of these factors may facilitate development of immunotherapy for gliomas as immunomodulatory and immune evasion mechanisms employed by malignant gliomas pose an appalling challenge to brain tumor immunotherapy.
Mechanisms of malignant glioma immune resistance and sources of immunosuppression
Gene therapy & molecular biology, 2006
High grade malignant gliomas are genetically unstable, heterogeneous and highly infiltrative; all characteristics that lend glioma cells superior advantages in resisting conventional therapies. Unfortunately, the median survival time for patients with glioblastoma multiforme remains discouraging at 12-15 months from diagnosis. Neuroimmunologists/oncologists have focused their research efforts to harness the power of the immune system to improve brain tumor patient survival. In the past 30 years, small numbers of patients have been enrolled in a plethora of experimental immunotherapy Phase I and II trials. Some remarkable anecdotal responses to immune therapy are evident. Yet, the reasons for the mixed responses remain an enigma. The inability of the devised immunotherapies to consistently increase survival may be due, in part, to intrinsically-resistant glioma cells. It is also probable that the tumor compartment of the tumor-bearing host has mechanisms or produces factors that prom...