Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them

Habashy, Karl John; Moussalem, Charbel; Sawaya, Raymond; Massaad, Michel J.

doi:10.1038/s41416-022-01864-w

Cited by 35 publications

(27 citation statements)

References 189 publications

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“…Owing in part to the existence of a highly immunosuppressive tumor microenvironment, immunotherapy trials for the treatment of glioma has proven largely unsuccessful, conferring little to no effect on overall survival 35,36 . Prior research in the field of tumor immunology has sought to characterize the molecular mechanisms employed by glioma cells that mediate this immunosuppressive constituency and has implicated anergic and regulatory T cells as important mediators of these processes 37,38 .…”

Section: Discussionmentioning

confidence: 99%

“…2-photon in vivo imaging 2-photon images of calcium reporter activity were assessed according to previously published protocols 61 . Briefly, calcium reporter activity was acquired using a Prairie Ultima IV 2-photon microscope through a 25× objective, 1.1 NA, or a 16× objective, 0.8 NA, at 920 nm (GCaMP) under spiral (10-20 Hz frame rate) or resonant scan mode (30)(31)(32)(33)(34)(35). A 525/70 nm emission filter was used for GCaMP indicators, and a 620/60 nm filter for mCherry emission.…”

Section: Intracranial Viral Injectionsmentioning

confidence: 99%

“…Owing in part to the existence of a highly immunosuppressive tumour microenvironment, immunotherapy trials for glioma have been largely unsuccessful, with little to no overall survival benefits 42,43 . Prior tumour immunology research has characterized the molecular mechanisms mediating this immunosuppressive environment in glioma, implicating anergic and regulatory T cells as important mediators 44,45 .…”

Section: Alts Enable Antitumor T Cell Responsesmentioning

confidence: 99%

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Identification of functional immune and neuronal tumour cells in glioma

Curry

McDonald

et al. 2022

Preprint

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Despite advances in cancer molecular profiling, successful therapeutic development has been hindered by challenges in identifying tumor-specific mechanisms that can be targeted without consequence to healthy tissue. Discrimination between tumor and host cells that comprise the tumor microenvironment remains a difficult yet important task for defining tumor cell signatures. Correspondingly, a computational framework capable of accurately distinguishing tumor from non-tumor cells has yet to be developed. Cell annotation algorithms are largely unable to assign integrated genomic and transcriptional profiles to single cells on a cell-by-cell basis. To address this, we developed the Single Cell Rule Association Mining (SCRAM) tool that integrates RNA-inferred genomic alterations with co-occurring cell type transcriptional signatures for individual cells. Applying our pipeline to human and mouse glioma, we identified tumor cell trajectories that recapitulate temporally-restricted developmental paradigms and feature unique co-occurring genomic and transcriptomic identities. Specifically, we describe and validate two previously unreported tumor cell populations with immune and neuronal signatures as hallmarks of human glioma subtypes. In vivo modeling revealed an immune-like tumor cell population can direct CD8+ T cell responses and survival outcomes. In parallel, electrophysiology and Patch-seq studies in human tumors confirmed a frequent subset of neuronal-like glioma cells that fire action potentials but retain the morphology of glia. These collective studies report the existence of new glioma cell types with functional properties akin to their non-tumor analogs and demonstrate the ability of SCRAM to identify and characterize these cell types in unprecedented detail.

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Section: Discussionmentioning

confidence: 99%

Section: Intracranial Viral Injectionsmentioning

confidence: 99%

Section: Alts Enable Antitumor T Cell Responsesmentioning

confidence: 99%

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Identification of functional immune and neuronal tumour cells in glioma

Curry

McDonald

et al. 2022

Preprint

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“…VEGF inhibitors (27), and later, bevacizumab (BVZ), a monoclonal antibody was approved for GBM treatment(28). However, the recurrence of GBM remained a major constraint(29–31). Besides, TMZ exerts immunomodulatory effects on the TIME.…”

Section: Discussionmentioning

confidence: 99%

An explainable artificial intelligence-based typification of chronic inflammatory responses enhances glioma prognosis

Chowdhury

Yip

et al. 2023

Preprint

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Glioma is one of the most aggressive solid brain tumors with a poor prognosis. A chronic tumor inflammatory microenvironment drives glioma promotion and progression. The neutrophil-to-lymphocyte ratio and other clinicopathological variables usually serve as prognostic glioma markers. However, they are not ubiquitous prognostic markers for glioma as they fail to reveal the intricacy between the glioma-specific tumor inflammatory microenvironment and the systemic inflammatory responses, especially those chronic inflammatory responses, which vary among individuals fabricating diverse prognostic outcomes. Here, we introduced an explainable artificial intelligence model to typify chronic inflammatory responses as prognostic markers for glioma using 694-patients’ data from The Cancer Genome Atlas. We characterized the glioma-specific personalized inflammatory mediators using multi-layered regulators such as transcriptional networks, cellular infiltration markers, and cellular senescence markers, which identified five unique chronic inflammatory responses (p-value<0.0001). We defined its prognostic significance using overall survival analyses. The chronic inflammatory responses were positively correlated with poor overall survival in glioma. The patients with higher chronic inflammatory responses showed significantly shorter overall survival than those with lower chronic inflammatory responses. Interestingly, optimizing those chronic inflammatory responses improved the overall survival of glioma patients. We identified the effector genes within the personalized inflammatory mediators’ networks, indicating them as the targets for optimizing individualized chronic inflammatory response profiles through co-drug intervention.SignificanceExplainable artificial intelligence-based typification of chronic inflammatory responses accelerates glioma prognosis and supports co-drug discovery to modulate inflammatory responses alongside cancer therapy, suggested by 694-glioma patients’ data analysis.

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“…New molecular regulators targeting SIRTs in GB have demonstrated favorable results in vivo and in vitro ( Table 1 ). Unfortunately, these do not translate into immediate success in clinical practice because of multiple factors, including tumor specificity and heterogeneity, stemness, blood–brain barrier drug penetration capacity, and interactions with the microenvironment [ 175 , 176 , 177 ]. At present, none of the SIRT inhibitors/activators are under clinical trial for GB [ 178 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

Kunadis

Piperi

2022

IJMS

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Recent advances in glioblastoma (GB) research have shed light on the molecular characteristics, the defected intracellular signaling pathways, and the genetic and epigenetic alterations involved in their pathogenesis. Despite constant efforts, GB remains an aggressive malignant tumor with limited therapeutic approaches, poor prognosis, and a low survival rate. Emerging evidence points towards the crucial impact of epigenetic post-translational modifications in cancer development with emphasis on the regulatory role of histone deacetylation in several key cellular processes, including metabolic pathways, regulation of stress response, senescence, proliferation, DNA repair, and apoptosis. The silent information regulator proteins (Sirtuins) are deacetylases of histone and non-histone proteins that have been recently implicated in the initiation as well as in the progression of GB. Herein, we provide a critical overview of the emerging functional role and mechanism of action of the seven Sirtuins (SIRT1-7) in GB and discuss their potential targeting options in clinical practice.

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Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them

Cited by 35 publications

References 189 publications

Identification of functional immune and neuronal tumour cells in glioma

Identification of functional immune and neuronal tumour cells in glioma

An explainable artificial intelligence-based typification of chronic inflammatory responses enhances glioma prognosis

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

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