Advanced Molecular Characterization Using Digital Spatial Profiling Technology on Immunooncology Targets in Methylated Compared with Unmethylated IDH-Wildtype Glioblastoma

Barber, H; Tofias, A; Lander, Beatrice; Daniels, Aled; Gong, Jin; Ren, Yuqi; Ren, Xing; Liang, Yan; White, Paul; Kurian, Kathreena M.

doi:10.1155/2021/8819702

Cited by 9 publications

(6 citation statements)

References 36 publications

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“…DSP has been used in the field of cancer research to search for TME transcriptional profiling, and to identify predictive markers for prognosis, therapy response prediction, or clinical outcomes [26,[57][58][59][60][61][62]70,71,82]. Furthermore, DSP has been utilized to investigate TME heterogeneity [27,[37][38][39][40][83][84][85].…”

Section: Digital Spatial Analysismentioning

confidence: 99%

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Dam

Baars

Vercoulen

2022

Cancers

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The tumor microenvironment is a complex ecosystem containing various cell types, such as immune cells, fibroblasts, and endothelial cells, which interact with the tumor cells. In recent decades, the cancer research field has gained insight into the cellular subtypes that are involved in tumor microenvironment heterogeneity. Moreover, it has become evident that cellular interactions in the tumor microenvironment can either promote or inhibit tumor development, progression, and drug resistance, depending on the context. Multiplex spatial analysis methods have recently been developed; these have offered insight into how cellular crosstalk dynamics and heterogeneity affect cancer prognoses and responses to treatment. Multiplex (imaging) technologies and computational analysis methods allow for the spatial visualization and quantification of cell–cell interactions and properties. These technological advances allow for the discovery of cellular interactions within the tumor microenvironment and provide detailed single-cell information on properties that define cellular behavior. Such analyses give insights into the prognosis and mechanisms of therapy resistance, which is still an urgent problem in the treatment of multiple types of cancer. Here, we provide an overview of multiplex imaging technologies and concepts of downstream analysis methods to investigate cell–cell interactions, how these studies have advanced cancer research, and their potential clinical implications.

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Section: Digital Spatial Analysismentioning

confidence: 99%

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Dam

Baars

Vercoulen

2022

Cancers

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“…NanoString GeoMx DSP technology allows for digital quantification of multiple proteins from a single FFPE tumour tissue, enabling simultaneous quantification of target proteins and the comparison of expression levels in different ROIs. Researchers have applied this technology to various types of tumours, including brain tumours, non-small cell lung cancer, melanoma, and breast cancer [19][20][21][22]. OPAL mIHC has been a widely used method for the comparison of TIM in GCs [23][24][25].…”

Section: S Choi H Kim Et Almentioning

confidence: 99%

PIK3CA mutation subtype delineates distinct immune profiles in gastric carcinoma

Choi

Kim

Heo

et al. 2023

The Journal of Pathology

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PIK3CA mutations in cancer regulate tumour immunogenicity. Given that PIK3CA mutation subtypes influence therapeutic responses to AKT inhibitor and that H1047R mutation confers selective growth advantages after immunotherapy, we hypothesised that immune phenotypes may depend on PIK3CA mutation subtypes. We investigated 133 gastric cancers (GCs) harbouring PIK3CA mutation [21 E542K (15.8%), 36 E545X (27.1%), 26 H1047X (19.5%), and 46 others (34.6%)]. Four patients (3.0%) had a combination of mutations (E542K + E545K in 3 patients and E545K + H1047R in 1 patient). Epstein-Barr virus (EBV) and microsatellite instability (MSI) status, PD-L1 (programmed death-ligand 1) combined positive score (CPS), and stromal tumour-infiltrating lymphocytes (TILs) were assessed. Concurrent genomic alterations, GeoMx digital spatial profiling (DSP), and OPAL multiplex immunohistochemistry (mIHC) were analysed, and correlation between the two assays was investigated. Of the 133 PIK3CA-mutant (PIK3CA m ) GCs, MSI-high GC was significantly frequent in the H1047X mutation subtype (p = 0.005), while EBV positivity did not affect the mutation subtypes. There was no significant survival difference between the E542K, E545X, and H1047X subgroups. However, in the subgroup analysis for EBV-positive GC, H1047X m GC showed a trend towards shorter survival than E542K and E545X m GC (p = 0.090 and 0.062). With DSP analysis, H1047X m GC showed elevated VISTA (p = 0.0003), granzyme B (p < 0.0001), CD4 (p = 0.0001), and CD45 (p < 0.0001) expression compared with the E542K m or E545X m GC subgroups, and only VISTA expression remained significant (p < 0.0001) using OPAL mIHC. DSP and OPAL analyses showed a moderate correlation of CD4 (ρ = 0.42, p = 0.004) and CD8 (ρ = 0.62, p < 0.001) expression levels in a comparison of six antibodies. Immune-related protein expression levels were evident when classified by the three PIK3CA hotspot mutations, and H1047X m GC showed the highest immune-related protein expression compared with E542K m or E545X m GC. Our results demonstrated distinct immune profiles in GC with PIK3CA hotspot mutations using GeoMx DSP and OPAL mIHC, and there was a correlation between the two multiplex platforms.

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“…Barber et al. also conducted a spatial transcriptomics study comparing core and periphery of GBM IDH-WT samples that were either MGMT methylated or unmethylated ( 94 ). They found a significant increase in proteins such as CD4, CD14, CD68, CD8A, B7-H3, PDL-1, CD19, FOXP3, CD44, and STAT3 was associated within the cores of methylated tumors but not unmethylated tumors.…”

Section: Spatial Transcriptomics In Glioblastomamentioning

confidence: 99%

Spatial transcriptomics in glioblastoma: is knowing the right zip code the key to the next therapeutic breakthrough?

Shireman,

Cheng,

Goel

et al. 2023

Front. Oncol.

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Spatial transcriptomics, the technology of visualizing cellular gene expression landscape in a cells native tissue location, has emerged as a powerful tool that allows us to address scientific questions that were elusive just a few years ago. This technological advance is a decisive jump in the technological evolution that is revolutionizing studies of tissue structure and function in health and disease through the introduction of an entirely new dimension of data, spatial context. Perhaps the organ within the body that relies most on spatial organization is the brain. The central nervous system’s complex microenvironmental and spatial architecture is tightly regulated during development, is maintained in health, and is detrimental when disturbed by pathologies. This inherent spatial complexity of the central nervous system makes it an exciting organ to study using spatial transcriptomics for pathologies primarily affecting the brain, of which Glioblastoma is one of the worst. Glioblastoma is a hyper-aggressive, incurable, neoplasm and has been hypothesized to not only integrate into the spatial architecture of the surrounding brain, but also possess an architecture of its own that might be actively remodeling the surrounding brain. In this review we will examine the current landscape of spatial transcriptomics in glioblastoma, outline novel findings emerging from the rising use of spatial transcriptomics, and discuss future directions and ultimate clinical/translational avenues.

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Advanced Molecular Characterization Using Digital Spatial Profiling Technology on Immunooncology Targets in Methylated Compared with Unmethylated IDH-Wildtype Glioblastoma

Cited by 9 publications

References 36 publications

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

PIK3CA mutation subtype delineates distinct immune profiles in gastric carcinoma

Spatial transcriptomics in glioblastoma: is knowing the right zip code the key to the next therapeutic breakthrough?

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