The REMBRANDT study, a large collection of genomic data from brain cancer patients

Gusev, Yuriy; Bhuvaneshwar, Krithika; Song, Lei; Zenklusen, Jean-Claude; Fine, Howard A.; Madhavan, Subha

doi:10.1038/sdata.2018.158

Cited by 136 publications

(131 citation statements)

References 17 publications

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“…e). To confirm this we used microarray data from the REMBRANDT study and GZMA gene expression as a simple surrogate for immune infiltration . This analysis confirmed the significantly higher expression of multiple immunosuppressive functions in patients with increased expression of anti‐tumour effector functions (Supporting information, Fig.…”

Section: Resultsmentioning

confidence: 70%

“…To compare the expression of selected genes in different patient groups we used RNAseq data from TCGA [obtained via The Cancer Imaging Archive (TCIA) ], assigning patients to either CIC2 or CIC4 (as above). In addition, we used microarray data from the REMBRANDT study downloaded from Betastasis.com. For REMBRANDT, patient samples were classified as granzyme A (GZMA) high expressors or GZMA low expressors based on the median expression value ( n = 214).…”

Section: Methodsmentioning

confidence: 99%

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Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Stead

Nsengimana

et al. 2019

Clinical and Experimental Immunology

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Summary Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem‐like cells, a source of post‐treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM‐infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)‐β‐mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single‐cell transcriptomics demonstrated that both tumour and haematopoietic‐derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co‐expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti‐tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

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Section: Resultsmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Stead

Nsengimana

et al. 2019

Clinical and Experimental Immunology

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“…LGALS9) and FOXP3 were also expressed at significantly higher levels in CIC2 than CIC4 ( Figure 4D), as were genes encoding soluble mediators of immunosuppression such IL10, TGFB1 and IDO1 ( Figure 4E). To confirm this we used microarray data from the REMBRANDT study (17) and GZMA gene expression as a simple surrogate for immune infiltration (35). This analysis confirmed the significantly higher expression of multiple immunosuppressive functions in patients with increased expression of anti-tumour effector functions (Supplementary Figure 6).…”

Section: A Spectrum Of Immune Activity In Gbm Patientsmentioning

confidence: 72%

“…To compare expression of selected genes in different patient groups we used RNAseq data from TCGA (obtained via TCIA (7)), assigning patients to either CIC2 or CIC4 (as above). In addition, we used microarray data from the REMBRANDT study (17) downloaded from Betastasis.com. For REMBRANDT, patient samples were classified as GZMA high expressors or GZMA low expressors based on the median expression value (n=214).…”

Section: Differential Expression Of Genes In Gbm Cic2 and Cic4 And Inmentioning

confidence: 99%

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Nsengimana

Reilly

et al. 2019

Preprint

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Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To better understand this problem we used a combination of NK cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment.In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of TGF-b mediated inhibition. This NK cell inhibition is accompanied by expression of mutiple immune checkpoint molecules on T cells. Single cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognised by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more likely benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

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“…To assess gene expression in human glioma samples, public expression datasets 369 GSE50161 (Griesinger et al, 2013), GSE36245 (Sturm et al, 2012), GSE16011 370 (Gravendeel et al, 2009), GSE7696 (Murat et al, 2008), GSE43378 (Kawaguchi et al, 371 2013), GSE53733 (Reifenberger et al, 2014), GSE57872 (Patel et al, 2014), 372 GSE108474 (Gusev et al, 2018), GSE118793, GSE4290 (Sun et al, 2006), GSE89567 373 (Venteicher et al, 2017), and TCGA (Brennan et al, 2013) were analysed and 374 visualised using the R2: microarray analysis and visualization platform 375 (http://r2.amc.nl) as previously described (Bunt et al, 2010). Gene set enrichment 376 analyses were performed using The Database for Annotation, Visualization and 377…”

mentioning

confidence: 99%

Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma

Chen

Bunt

Bridges

et al. 2019

Preprint

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40Astrocytomas are composed of heterogeneous cell populations. Compared to grade IV 41 glioblastoma, low-grade astrocytomas have more differentiated cells and are associated 42 with a better prognosis. Therefore, inducing cellular differentiation may serve as a 43 therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for 44 normal astrocytic differentiation and therefore could be effectors of cellular 45 differentiation in glioblastoma. We analysed expression of family members NFIA and 46 NFIB using high-grade astrocytoma mRNA expression datasets, and with 47 immunofluorescence co-staining. Their expression is reduced in glioblastomas and is 48 associated with differentiated and mature astrocyte-like cells at a cellular level. 49Furthermore, induction of NFI expression is sufficient to promote cellular 50 differentiation in patient-derived glioblastoma xenografts. Our findings indicate that 51 NFI proteins may have an endogenous pro-differentiative function in astrocytomas, 52 similar to their role in normal development. Overall, our study establishes a basis for 53 further investigation of targeting NFI-mediated differentiation as a potential 54 differentiation therapy. 55 56 57 mechanism by which tumour cells evade differentiation and thereby remain 103 proliferative. This is in line with studies which report that the Nfi loci are common 104 insertion sites in insertional mutagenesis mouse models of gliomas, suggesting that 105 reduced expression promotes tumorigenicity (Johansson et al., 2004; Vyazunova et al., 106 2014). 107

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The REMBRANDT study, a large collection of genomic data from brain cancer patients

Cited by 136 publications

References 17 publications

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma

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