RESUMO
BACKGROUND: Glioblastoma is a highly aggressive type of brain tumor 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 tumor 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 tumor cells and the tumor microenvironment in response to nivolumab. Moreover, nivolumab-treatment was associated with an increased transition to mesenchymal stem-like tumor cells, and an increase in TAMs and exhausted and proliferative T cells. We verify and extend our findings in large external glioblastoma dataset (nâ =â 298), develop a latent immune signature and find 18% of primary glioblastoma samples to be latent immune, associated with mesenchymal tumor cell state and TME immune response. Finally, we show that latent immune glioblastoma patients are associated with shorter overall survival following immune checkpoint treatment (Pâ =â .0041). CONCLUSIONS: We find a resistance mechanism signature in one fifth of glioblastoma patients associated with a tumor-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 tumor cells.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Imunoterapia , Microambiente Tumoral , Humanos , Glioblastoma/imunologia , Glioblastoma/patologia , Glioblastoma/terapia , Glioblastoma/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Nivolumabe/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Células-Tronco Mesenquimais/imunologia , Prognóstico , Taxa de Sobrevida , Biomarcadores Tumorais/genética , FemininoRESUMO
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.