Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy

K White¹, K Connor¹, M Meylan², A Bougoüin², M Salvucci¹, F Bielle³, A C O'Farrell¹, K Sweeney⁴, L Weng⁵, G Bergers⁵, P Dicker⁶, D M Ashley⁷, E S Lipp⁷, J T Low⁷, J Zhao⁸, P Wen⁹, R Prins¹⁰, M Verreault³, A Idbaih¹¹, A Biswas¹, J H M Prehn¹, D Lambrechts¹², I Arijs¹², F Lodi¹², G Dilcan¹², M Lamfers¹³, S Leenstra¹³, F Fabro¹³, I Ntafoulis¹³, J M Kros¹⁴, J Cryan¹⁵, F Brett¹⁵, E Quissac³, A Beausang¹⁵, S MacNally⁴, P O'Halloran⁴, J Clerkin⁴, O Bacon¹⁵, A Kremer¹⁶, R T Chi Yen¹⁶, F S Varn¹⁷, R G W Verhaak¹⁸, C Sautès-Fridman², W H Fridman², A T Byrne¹⁹

Affiliations

¹ Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
² Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université de Paris, Paris, France.
³ Paris Brain Institute (ICM), CNRS UMR 7225, Inserm U 1127, UPMC-P6 UMR S 1127, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁴ National Centre of Neurosurgery, Beaumont Hospital, Dublin, Ireland.
⁵ VIB-KU Leuven Center for Cancer Biology, Department of Oncology, Leuven, Belgium.
⁶ Epidemiology & Public Health, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁷ Duke Cancer Institute, Duke University, Durham, USA.
⁸ Department of Systems Biology at Columbia University, New York, USA.
⁹ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, USA.
¹⁰ Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, USA.
¹¹ Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France.
¹² Laboratory for Translational Genetics, Department of Human Genetics, Leuven, Belgium; VIB Center for Cancer Biology, Leuven, Belgium.
¹³ Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁴ Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁵ Department of Neuropathology, Beaumont Hospital, Dublin, Ireland.
¹⁶ Information Technology for Translational Medicine (ITTM), Luxembourg, Luxembourg.
¹⁷ The Jackson Laboratory for Genomic Medicine, Farmington, USA.
¹⁸ The Jackson Laboratory for Genomic Medicine, Farmington, USA; Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, the Netherlands.
¹⁹ Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland. Electronic address: annettebyrne@rcsi.ie.

PMID: 36494005
DOI: 10.1016/j.annonc.2022.11.008

Free article

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy

K White et al. Ann Oncol. 2023 Mar.

Free article

. 2023 Mar;34(3):300-314.

doi: 10.1016/j.annonc.2022.11.008. Epub 2022 Dec 6.

Authors

Affiliations

¹ Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
² Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université de Paris, Paris, France.
³ Paris Brain Institute (ICM), CNRS UMR 7225, Inserm U 1127, UPMC-P6 UMR S 1127, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁴ National Centre of Neurosurgery, Beaumont Hospital, Dublin, Ireland.
⁵ VIB-KU Leuven Center for Cancer Biology, Department of Oncology, Leuven, Belgium.
⁶ Epidemiology & Public Health, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁷ Duke Cancer Institute, Duke University, Durham, USA.
⁸ Department of Systems Biology at Columbia University, New York, USA.
⁹ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, USA.
¹⁰ Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, USA.
¹¹ Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France.
¹² Laboratory for Translational Genetics, Department of Human Genetics, Leuven, Belgium; VIB Center for Cancer Biology, Leuven, Belgium.
¹³ Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁴ Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁵ Department of Neuropathology, Beaumont Hospital, Dublin, Ireland.
¹⁶ Information Technology for Translational Medicine (ITTM), Luxembourg, Luxembourg.
¹⁷ The Jackson Laboratory for Genomic Medicine, Farmington, USA.
¹⁸ The Jackson Laboratory for Genomic Medicine, Farmington, USA; Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, the Netherlands.
¹⁹ Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland. Electronic address: annettebyrne@rcsi.ie.

PMID: 36494005
DOI: 10.1016/j.annonc.2022.11.008

Abstract

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.

Results: TME^High tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TME^High/mesenchymal+ patients featured tertiary lymphoid structures. TME^Med (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TME^Low (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TME^High patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TME^High patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival.

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.

Keywords: IDHwt glioblastoma; immunotherapy; precision therapy; subtypes; tumour microenvironment.

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Disclosure The authors have declared no conflicts of interest.

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Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy

Affiliations

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous