Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

Abstract

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.

Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma

“…Of note, a recent comparative single cell multi-omic study in adult glioblastoma found conserved changes in tumor-associated immune cell responses to therapy between mouse models and patient tumors, suggesting that animal studies have the potential to accurately recapitulate certain aspects of patient tumor microenvironment ( Pombo Antunes et al, 2021 ). Given that glioblastoma driver mutations are known to influence the immune composition of the tumor microenvironment in adult HGG ( Garcia-Fabiani et al, 2021 ), additional comparative studies using single cell multi-omic techniques to analyze recently developed immunocompetent models of pHGG may therefore provide insight into the effects of patient tumor subtype on therapy resistance due to immunosuppressive or immunostimulatory states ( Chen and Hambardzumyan, 2018 ; Patel et al, 2020 ; Tomita et al, 2022 ). Together, these studies emphasize how combining data from multi-omic single cell profiling of patient samples and results obtained from preclinical model systems may help researchers to better understand the significance of specific molecular profiles on glioma cell behaviors like drug resistance or response to immunotherapy.…”

TSPO PET signal using [18F]GE180 is associated with survival in recurrent gliomas

“…As a microglia activation marker, TSPO PET visualizes neuroinflammation and has been established as a tool for imaging inflammatory CNS processes in neurodegenerative diseases [40,41] or in multiple sclerosis [13,42]. In the tumor microenvironment, inflammatory processes are increasingly recognized to play a role in gliomagenesis [43], treatment resistance [44], and tumor recurrence [12,45]. As effectors of these processes, immunosuppressive myeloid-derived suppressor cells and regulatory T-cells outweigh activating immune effector cells such as T-cells and natural killer cells [46][47][48][49].…”

“…Yet, heterogeneity is not only seen between different molecular tumor entities, but also both spatially and temporally within the same tumor [50]. This heterogeneity adds to the difficulty of therapeutically stimulating an anti-glioma immune response [44]. Therefore, illustrating the tumor immune environment in vivo and monitoring changes over time is promising for prognostication and especially in light of recent advances in immunomodulating therapies [51].…”

Modeling Glioma Oncostreams In Vitro: Spatiotemporal Dynamics of their Formation, Stability, and Disassembly

“…(10)(11)(12)(13) The standard of care, involving surgical resection, radiotherapy, and chemotherapy, has made little progress in improving long-term survival over the past two decades. (14)(15)(16)(17) In the United States, Tumor-Treating Fields (TTFs) have been introduced as an optional treatment for GBM, demonstrated improved progression-free and overall survival in a phase III trial (NCT00916409). (18,19) This highlights the importance for a deeper, more refined understanding of the complex spatiotemporal glioma dynamics.…”