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Glioblastoma Omics Study Highlights Informative Tumor Features, Immune Subtypes

NEW YORK – A team from Washington University, the Pacific Northwest National Laboratory, and elsewhere has identified immune subgroups in glioblastoma (GBM) that may ultimately help in developing more effective immunotherapy approaches against the aggressive brain cancer.

"To improve therapies for this deadly cancer, understanding the tumor cells themselves is important but not enough," co-senior and -corresponding author Li Ding, a medicine and genetics researcher at WashU, director of computational biology for its oncology division, and assistant director of the McDonnell Genome Institute, said in a statement. "We also must understand the tumor cells' interactions with the surrounding environment, including immune cells and the connective tissues and blood vessels." 

With that in mind, the researchers used whole-genome sequencing, exome sequencing, RNA sequencing, microRNA-seq, single-nuclei RNA-seq, array-based methylation profiling, mass spectrometry, and other approaches to assess genomic, metabolomic, proteomic, and post-translational modification patterns in 99 untreated GBM tumors and 10 normal, non-matched brain samples. Their findings, published in Cancer Cell on Thursday, pointed to four GBM immune subtypes for the nervous system cancer, including an immune subtype enriched for tumors with IDH mutations.

Such findings "might have potential implications in stratifying patients for clinical trials and treatments," Ding explained in an email.

One of the immune subgroups was marked by a dearth of T cells and high levels of infiltrating macrophage immune cells, for example, while another immune subtype was enriched for T lymphocyte and natural killer cell levels and IDH mutations but was poor in macrophage-microglia immune cell infiltration. Yet another immune subtype had middling macrophage levels, the team noted, and a fourth immune subtype lacked significant levels of immune cells in general.

The investigators speculated that taking these distinct subtypes into account may spur more effective immune system-based treatments for the nervous system cancer, while making it possible to distinguish between cases expected to have better or worse responses to immunotherapy.

"Immunotherapy clinical trials in glioblastoma have been negative so far," co-author Albert Kim, a neurological surgery researcher at Washington University and director of the Siteman Cancer Center's Brain Tumor Center, said in a statement. "And the fact that there are four different immune subgroups may be one of the reasons behind that. We can't treat all glioblastoma tumors as one disease."

Beyond the immune subtype findings, the team's analyses revealed a range of informative GBM features — from changes in DNA repair pathway activity and potentially targetable oncogenic pathways to histone acetylation and phosphorylation shifts, including higher-than-usual levels of phosphorylation involving the PTPN11 and PLCG1 gene products.

"The multidimensional analysis … adds context to prior genomic and transcription-based investigations of GBM," the authors reported, "and suggests avenues for further mechanistic studies."

Ding noted that the investigators are currently following up on their current findings with a larger study encompassing tumors from a broader range of GBM patients, Ding said, including young adults with GBM and those with recurrent forms of the disease. 

"Rapid advancement of single-cell genomics and proteomics technologies will facilitate deeper analyses of GBM heterogeneity and [tumor microenvironment] interactions," Ding and her co-authors concluded. "We hope these advances will improve patient stratification for clinical trials and lead, ultimately, to personalized treatments."

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