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JGM, Humans, Glioblastoma, Tumor Microenvironment, Neoplasm Recurrence, Local, Immunotherapy, Brain Neoplasms

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Ann Oncol. 2023;34(3):300-14.







This project has received funding from the European Union’s Horizon 2020 and 2021 research and innovation programme under the Marie Skłodowska-Curie ITN initia- tives [grant number #766069], GLIOTRAIN (http://www. and ‘GLIORESOLVE’ projects [grant number #101073386]. Additional support was received by donation from the Paolo Iacovelli memorial endowment. We are also grateful for the financial support from the Beaumont Hos- pital Foundation, and from Brain Tumour Ireland to estab- lish the Beaumont Hospital Brain Tumour Biorepository. The authors further acknowledge financial contribution towards staff salaries from RCSI and Champions Oncology (Balti- more, USA).


BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies.

MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers.


CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.


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