Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery

Shekarian, Tala; Zinner, Carl; Bartoszek, Ewelina; Duchemin, Wandrille; Wachnowicz, Anna Teresa; Hogan, Sabrina A.; Etter, Manina Maja; Flammer, Julia; Paganetti, Chiara; Martins, Tomás A; Schmassmann, Philip; Zanganeh, Saeid; Goff, François Le; Muraro, Manuele Giuseppe; Ritz, Marie‐Françoise; Phillips, Darci; Bhate, Salil; Barlow, Graham L.; Nolan, Garry P.; Schürch, Christian M.; Hütter, Gregor

doi:10.1126/sciadv.abn9440

Cited by 38 publications

(30 citation statements)

References 51 publications

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“…PRRS was calculated for each type of TAMs. A previous study suggested that higher interferon γ (IFNγ) response was associated with immunotherapy response in GBM, and IFNγ could modulate the immune cell composition in the tumor center ( 44 ). Intriguingly, a significantly higher PRRS was found in interferon-signature microglial-TAM (IFN_MgTAM) than in non-interferon-signature microglial-TAM (MgTAM) ( Figure 7H, I ).…”

Section: Resultsmentioning

confidence: 99%

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

et al. 2022

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BackgroundPyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas.MethodsThe TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated.ResultsPatients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas.ConclusionThe pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

et al. 2022

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“…Response to the antidepressant Vortioxetine, the most promising preclinical candidate, was particularly aligned with aggressive GSC morphotypes present in patients with poor prognosis. These efforts contribute to the nascent community of glioblastoma research focusing on the investigation of patient-derived tumor explants that facilitate translational investigation of complex tumor behavior, including the development of genetically characterized patient cultures, organoid biobanks, and regionally annotated samples 29,[77][78][79][80][81][82] .…”

Section: Discussionmentioning

confidence: 99%

Targeting tumour-intrinsic neural vulnerabilities of glioblastoma

Lee

Weiss

Buehler

et al. 2022

Preprint

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Glioblastoma is the most common yet deadliest primary brain cancer. The neural behavior of glioblastoma, including the formation of synaptic circuitry and tumor microtubes, is increasingly understood to be pivotal for disease manifestation. Nonetheless, the few approved treatments for glioblastoma target its oncological nature, while its neural vulnerabilities remain incompletely mapped and clinically unexploited. Here, we systematically survey the neural molecular dependencies and cellular heterogeneity across glioblastoma patients and diverse model systems. In 27 patient tumor samples taken directly after surgery, we identify a spectrum of cancer cell morphologies indicative of poor prognosis and discover a set of repurposable neuroactive drugs with consistent anti-glioblastoma efficacy. Glioblastoma cells exhibit functional dependencies on highly expressed neuroactive drug targets, while interpretable molecular machine learning (COSTAR) reveals their downstream convergence on AP-1-driven tumor suppression. This drug-target connectivity signature is confirmed by highly accurate in silico drug screening on >1 million compounds using COSTAR, as well as by multi-omic profiling of drug-treated glioblastoma cells. Thus, Ca2+-driven AP-1 pathway induction represents a tumor-intrinsic vulnerability at the intersection of oncogenesis and neural activity-dependent signaling. Opportunities for clinical translation of this neural vulnerability are epitomized by the antidepressant Vortioxetine synergizing with current standard of care treatments in vivo. Together, the results presented here provide a mechanistic foundation and conceptual framework for the treatment of glioblastoma based on its neural origins.

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“…Furthermore, many studies have shown that the cultivation of patient-derived biopsies in perfusion bioreactors can maintain the same gene expression profile and drug resistance patterns recorded in vivo [ 95 ]. Models of colon cancer [ 96 , 97 ], breast carcinoma [ 95 , 98 , 99 , 100 ], ovarian cancer [ 101 ], bone metastatic prostate cancer [ 102 ], Erwin sarcoma [ 103 , 104 ], leukemia [ 105 , 106 ], and glioblastoma [ 107 ] have been engineered using perfusion bioreactors.…”

Section: 3d Modelsmentioning

confidence: 99%

“…There were then perfused with a mix of cell culture media and growth factors. In this model, it was shown that a subset of cells was prone to the emission of IFNγ and consequently to shifts in immune cell composition within specified tissue portions; immune responder and non-responder subpopulations could then be identified [ 107 ].…”

Section: 3d Modelsmentioning

confidence: 99%

In Vitro Veritas: From 2D Cultures to Organ-on-a-Chip Models to Study Immunogenic Cell Death in the Tumor Microenvironment

Krysko

Demuynck

Efimova

et al. 2022

Cells

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Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in vivo on mice, translation into the clinic remains challenging. A major hindrance in antitumor research is the poor predictive ability of classic 2D in vitro models, which do not consider tumor biological complexity, such as the contribution of the tumor microenvironment (TME), which plays a crucial role in immunosuppression and cancer evasion. In this review, we describe different tumor models, from 2D cultures to organ-on-a-chip technology, as well as spheroids and perfusion bioreactors, all of which mimic the different degrees of the TME complexity. Next, we discuss how 3D cell cultures can be applied to study ICD and how to increase the translational potential of the ICD inducers. Finally, novel research directions are provided regarding ICD in the 3D cellular context which may lead to novel immunotherapies for cancer.

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Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery

Cited by 38 publications

References 51 publications

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

Targeting tumour-intrinsic neural vulnerabilities of glioblastoma

In Vitro Veritas: From 2D Cultures to Organ-on-a-Chip Models to Study Immunogenic Cell Death in the Tumor Microenvironment

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