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BACKGROUND: Glioblastoma is a highly aggressive type of brain tumour for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected patients, and there is an urgent need to identify mechanisms of treatment resistance to design novel therapy strategies. METHODS: Here we investigated the phenotypic and transcriptional dynamics at single-cell resolution during nivolumab immune checkpoint treatment of glioblastoma patients. RESULTS: We present the integrative paired single-cell RNA-seq analysis of 76 tumour samples from patients in a clinical trial of the PD-1 inhibitor nivolumab and untreated patients. We identify a distinct aggressive phenotypic signature in both tumour cells and the tumour microenvironment in response to nivolumab. Moreover, nivolumab-treatment was associated with an increased transition to mesenchymal stem-like tumour cells, and an increase in TAMs and exhausted and proliferative T cells. We verify and extend our findings in large external glioblastoma dataset (n = 298), develop a latent immune signature and find 18% of primary glioblastoma samples to be latent immune, associated with mesenchymal tumour cell state and TME immune response. Finally, we show that latent immune glioblastoma patients are associated with shorter overall survival following immune checkpoint treatment (p = 0.0041). CONCLUSIONS: We find a resistance mechanism signature in a quarter of glioblastoma patients associated with a tumour-cell transition to a more aggressive mesenchymal-like state, increase in TAMs and proliferative and exhausted T cells in response to immunotherapy. These patients may instead benefit from neuro-oncology therapies targeting mesenchymal tumour cells.
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Background: Glioblastoma is an aggressive brain cancer with no possibility for cure. Treatment and survival have only improved slightly since 2005 when the current regime was implemented. The limited improvements in the treatment of glioblastoma may reflect our poor understanding of the disease. We hypothesize that systematically collected translational data will improve knowledge and hereby treatment. Methods: We have been performing whole exome sequencing in glioblastoma tumor tissue since 2016 and whole genome sequencing (WGS) since 2020 with the aim of offering experimental treatment. Results: We have sequenced 400+ GBM patients and from these 100+ are paired tumor samples from relapse surgery. To develop genomic profiling and to increase the information on each patient´s contribution, we have initiated the Neurogenome study as of June 2022. The Neurogenome protocol is a national, comprehensive, translational, and omic protocol. It is a continuation of 2 previous protocols from 2016 and forth in our department, but with more substudies added, focusing on the translational and clinical utility. We collect and analyze data from an out-patient clinic in a systematic approach to a number of subprojects ranging from basic science to applied clinical science, including clinical trials. Conclusions: The protocol will act as a backbone for future projects in the national research center, Danish Comprehensive Cancer Center-Brain Tumor Center with the overall aim to select eligible patients for experimental treatment based upon genomic alterations. The article will present the Neurogenome setup and a presentation of selected projects that are based upon inclusion.
