TMIC-10 - Identification, validation and biological characterization of novel Glioblastoma Tumour Microenvironment subtypes: Implications for precision immunotherapy

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Author(s)

Kieron White

Dept Physiology and Medical Physics, Royal College of Surgeons in Ireland
Dublin, Ireland

Poster Presenter(s)

Kate Connor, BA(Mod), PhD (she/her/hers)

Dept Physiology and Medical Physics, Royal College of Surgeons in Ireland
Dublin, Ireland

Author(s)

MM

Maxime Meylan, PhD

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, 75006 Paris, France
Paris, France
AB

Antoine Bougoüin

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, 75006 Paris, France
Paris, France
MS

Manuela Salvucci, PhD

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Dublin, Ireland
Franck Bielle, MD, PhD (he/him/his)

Sorbonne Université, Paris Brain Institute
Paris, France
AO

Alice C. O’Farrell

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Dublin, Ireland
KS

Kieron J. Sweeney

Department of Neurosurgery, Beaumont hospital
Dublin, Ireland
LW

Linqian Weng

VIB-KU Leuven Center for Cancer Biology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium
Leuven, Belgium
GB

Gabriele Bergers

VIB-KU Leuven Center for Cancer Biology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium
Leuven, Belgium
PD

Patrick Dicker

Epidemiology & Public Health, Royal College of Surgeons in Ireland, Dublin, Ireland
Dublin, Ireland
David M. Ashley, MBBS (Hon), FRACP, PhD

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
Durham, United States
EL

Eric S. S. Lipp, MD

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center
Durham, United States
Justin T. Low, M.D., Ph.D.

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center
Durham, United States
JZ

Junfei Zhao, PhD

Department of Systems Biology at Columbia University, New York, NY, 10032, USA
New York, United States
Patrick Y. Wen, MD

Dana-Farber Cancer Institute
Boston, United States
Robert M. Prins, PhD

University of California, Los Angeles
Los Angeles, United States
MV

Maite Verreault, PhD

Paris Brain Institute (ICM), CNRS UMR 7225, Inserm U 1127, UPMC-P6 UMR S 1127, Hôpital de la Pitié - Salpêtrière - 47, boulevard de l'Hôpital –75013 Paris
Paris, France
Ahmed Idbaih, MD, PhD

Sorbonne Université, AP-HP, ICM, Hôpital Universitaire La Pitié-Salpêtrière
Paris, France
JP

Jochen Prehn, PhD

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York Street, Dublin 2
Dublin, Ireland
Frederick S. Varn, PhD

The Jackson Laboratory
Farmington, United States
Roel Verhaak, PhD

The Jackson Laboratory
Farmington, United States
CS

Catherine Sautès-Fridman, PhD

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, 75006 Paris, France
Paris, France
WF

Wolf H. Fridman, MD, PhD

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, 75006 Paris, France
Paris, France
AB

Annette T. Byrne, PhD

Dept Physiology and Medical Physics, Royal College of Surgeons in Ireland
Dublin, Ireland

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 hypothesized that interrogation of the GBM tumor microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision treatment strategies. To this end, a refined and validated microenvironment cell population (MCP)-counter method was applied to > 800 GBM patient tumours and validated by multiplex-immunohistochemistry. The MCP-counter deconvolution method interrogates the TME composition from transcriptomic data. Using this refined method, we classified the GLIOTRAIN(www.gliotrain.eu) IDHwt GBM cohort (n=123) into 3 novel clusters characterised by differences in TME composition and subsequently validated findings in the TCGA (n=69), CGGA (n=72) and DUKE (unpublished)(n=162) cohorts. TME^High tumours (30%) displayed elevated immune populations, functional orientation markers, immune checkpoint genes, and upregulated immunoregulatory pathways. Moreover, tertiary lymphoid structures were a feature of TME^High/mesenchymal⁺ patients. TME^Med (46%) tumours displayed heterogeneous immune populations and upregulated neuronal signalling pathways. TME^Low (24%) tumours represented an ‘immune-desert’ group, high EGFR mutation frequency and upregulated EGFR signalling pathways. Longitudinal analysis of the GLASS cohort revealed TME-subtype transitions upon recurrence, influenced by TME composition changes. Finally, assessment of three GBM immunotherapy clinical trial cohorts revealed that TME^High patients treated with neo-adjuvant anti-PD1 have a significantly improved survival (P=0.04). Moreover, TME^High patients treated with anti-PD1 and an oncolytic virus (PVSRIPO) in the adjuvant setting, showed a trend towards improved survival (P=0.15 and P=0.056 respectively). Overall, we have established a novel TME-based classification system for application in intracranial malignancies. This system may be used to better inform a precision targeting approach in the brain tumour setting. For example, we hypothesise that patients bearing TME^Low tumours may be amenable to neoadjuvant anti-TIM3 + EGFR inhibitor, TME^Med to anti-angiogenic immunotherapy, and TME^High patients to neoadjuvant anti-PD1 + anti-CTLA4.