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

被引：61

作者：

White, K. ^{[1
]}

Connor, K. ^{[1
]}

Meylan, M. ^{[2
]}

Bougouein, A. ^{[2
]}

Salvucci, M. ^{[1
]}

Bielle, F. ^{[3
]}

O'Farrell, A. C. ^{[1
]}

Sweeney, K. ^{[4
]}

Weng, L. ^{[5
]}

Bergers, G. ^{[5
]}

Dicker, P. ^{[6
]}

Ashley, D. M. ^{[7
]}

Lipp, E. S. ^{[7
]}

Low, J. T. ^{[7
]}

Zhao, J. ^{[8
]}

Wen, P. ^{[9
]}

Prins, R. ^{[10
]}

Verreault, M. ^{[3
]}

Idbaih, A. ^{[11
]}

Biswas, A. ^{[1
]}

Prehn, J. H. M. ^{[1
]}

Lambrechts, D. ^{[12
,13
]}

Arijs, I. ^{[12
,13
]}

Lodi, F. ^{[12
,13
]}

Dilcan, G. ^{[12
,13
]}

Lamfers, M. ^{[14
]}

Leenstra, S. ^{[14
]}

Fabro, F. ^{[14
]}

Ntafoulis, I. ^{[14
]}

Kros, J. M. ^{[15
]}

Cryan, J. ^{[16
]}

Brett, F. ^{[16
]}

Quissac, E. ^{[3
]}

Beausang, A. ^{[16
]}

MacNally, S. ^{[4
]}

O'Halloran, P. ^{[4
]}

Clerkin, J. ^{[4
]}

Bacon, O. ^{[16
]}

Kremer, A. ^{[17
]}

Yen, R. T. Chi ^{[17
]}

Varn, F. S. ^{[18
]}

Verhaak, R. G. W. ^{[18
,19
]}

Sautes-Fridman, C. ^{[2
]}

Fridman, W. H. ^{[2
]}

Byrne, A. T. ^{[1
]}

机构：

[1] Royal Coll Surgeons Ireland, Dept Physiol & Med Phys, Dublin, Ireland

[2] Sorbonne Univ, Univ Paris, Ctr Rech Cordeliers, INSERM,USPC, Paris, France

[3] Hop La Pitie Salpetriere, Paris Brain Inst ICM, CNRS UMR 7225, Inserm U 1127,UPMC P6 UMR S 1127, Paris, France

[4] Beaumont Hosp, Natl Ctr Neurosurg, Dublin, Ireland

[5] Katholieke Univ Leuven, Dept Oncol, Ctr Canc Biol, VIB, Leuven, Belgium

[6] Royal Coll Surgeons Ireland, Epidemiol & Publ Hlth, Dublin, Ireland

[7] Duke Univ, Duke Canc Inst, Durham, England

[8] Columbia Univ, Dept Syst Biol, New York, NY USA

[9] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med & Mol Pharmacol, Los Angeles, CA USA

[11] Sorbonne Univ, Hop Univ La Pitie Salpetriere Charles Foix, APHP, Inserm,CNRS,UMR S 1127,Paris Brain Inst ICM, Paris, France

[12] Lab Translat Genet, Dept Human Genet, Leuven, Belgium

[13] VIB Ctr Canc Biol, Leuven, Belgium

[14] Erasmus Univ, Brain Tumor Ctr, Dept Neurosurg, Med Ctr, Rotterdam, Netherlands

[15] Erasmus MC, Dept Pathol, Rotterdam, Netherlands

[16] Beaumont Hosp, Dept Neuropathol, Dublin, Ireland

[17] ITTM, Luxembourg, Luxembourg

[18] Jackson Lab Genom Med, Farmington, CT USA

[19] Univ Amsterdam, VU Univ, Canc Ctr Amsterdam,Med Ctr, Dept Neurosurg,Med Ctr, Amsterdam, Netherlands

来源：

ANNALS OF ONCOLOGY | 2023年 / 34卷 / 03期

关键词：

IDHwt glioblastoma; tumour microenvironment; subtypes; immunotherapy; precision therapy; IMMUNE; EXPRESSION; CELLS;

D O I：

10.1016/j.annonc.2022.11.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (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 TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh 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.

引用

页码：300 / 314

页数：15

共 50 条

[1] Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium [J].

Aldape, Kenneth ;

Amin, Samirkumar B. ;

Ashley, David M. ;

Barnholtz-Sloan, Jill S. ;

Bates, Amanda J. ;

Beroukhim, Rameen ;

Bock, Christoph ;

Brat, Daniel J. ;

Claus, Elizabeth B. ;

Costello, Joseph F. ;

de Groot, John F. ;

Finocchiaro, Gaetano ;

French, Pim J. ;

Gan, Hui K. ;

Griffith, Brent ;

Herold-Mende, Christel C. ;

Horbinski, Craig ;

Iavarone, Antonio ;

Kalkanis, Steven N. ;

Karabatsou, Konstantina ;

Kim, Hoon ;

Kouwenhoven, Mathilde C. M. ;

McDonald, Kerrie L. ;

Miletic, Hrvoje ;

Nam, Do-Hyun ;

Ng, Ho Keung ;

Niclou, Simone P. ;

Noushmehr, Houtan ;

Ormond, D. Ryan ;

Poisson, Laila M. ;

Reifenberger, Guido ;

Roncaroli, Federico ;

Sa, Jason K. ;

Smitt, Peter A. E. Sillevis ;

Smits, Marion ;

Souza, Camila F. ;

Tabatabai, Ghazaleh ;

Van Meir, Erwin G. ;

Verhaak, Roel G. W. ;

Watts, Colin ;

Wesseling, Pieter ;

Woehrer, Adelheid ;

Yung, W. K. Alfred ;

Jungk, Christine ;

Hau, Ann-Christin ;

van Dyck, Eric ;

Westerman, Bait A. ;

Yin, Julia ;

Abiola, Olajide ;

Zeps, Nikolaj .

NEURO-ONCOLOGY, 2018, 20 (07) :873-884

[2] Circulating biomarkers in patients with glioblastoma [J].

Bark, Juliana Muller ;

Kulasinghe, Arutha ;

Chua, Benjamin ;

Day, Bryan W. ;

Punyadeera, Chamindie .

BRITISH JOURNAL OF CANCER, 2020, 122 (03) :295-305

[3] Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression [J].

Becht, Etienne ;

Giraldo, Nicolas A. ;

Lacroix, Laetitia ;

Buttard, Benedicte ;

Elarouci, Nabila ;

Petitprez, Florent ;

Selves, Janick ;

Laurent-Puig, Pierre ;

Sautes-Fridman, Catherine ;

Fridman, Wolf H. ;

de Reynies, Aurelien .

GENOME BIOLOGY, 2016, 17

[4] Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma [J].

Berghoff, Anna Sophie ;

Kiesel, Barbara ;

Widhalm, Georg ;

Rajky, Orsolya ;

Ricken, Gerda ;

Woehrer, Adelheid ;

Dieckmann, Karin ;

Filipits, Martin ;

Brandstetter, Anita ;

Weller, Michael ;

Kurscheid, Sebastian ;

Hegi, Monika E. ;

Zielinski, Christoph C. ;

Marosi, Christine ;

Hainfellner, Johannes A. ;

Preusser, Matthias ;

Wick, Wolfgang .

NEURO-ONCOLOGY, 2015, 17 (08) :1064-1075

[5] cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas [J].

Brat, Daniel J. ;

Aldape, Kenneth ;

Colman, Howard ;

Figrarella-Branger, Dominique ;

Fuller, Gregory N. ;

Giannini, Caterina ;

Holland, Eric C. ;

Jenkins, Robert B. ;

Kleinschmidt-DeMasters, Bette ;

Komori, Takashi ;

Kros, Johan M. ;

Louis, David N. ;

McLean, Catriona ;

Perry, Arie ;

Reifenberger, Guido ;

Sarkar, Chitra ;

Stupp, Roger ;

van den Bent, Martin J. ;

von Deimling, Andreas ;

Weller, Michael .

ACTA NEUROPATHOLOGICA, 2020, 139 (03) :603-608

[6] Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma [J].

Brat, DJ ;

Van Meir, EG .

LABORATORY INVESTIGATION, 2004, 84 (04) :397-405

[7]

Bristol Myers Squibb, 2019, BRIST MYERS SQUIBB C

[8] Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states [J].

Chaligne, Ronan ;

Gaiti, Federico ;

Silverbush, Dana ;

Schiffman, Joshua S. ;

Weisman, Hannah R. ;

Kluegel, Lloyd ;

Gritsch, Simon ;

Deochand, Sunil D. ;

Castro, L. Nicolas Gonzalez ;

Richman, Alyssa R. ;

Klughammer, Johanna ;

Biancalani, Tommaso ;

Muus, Christoph ;

Sheridan, Caroline ;

Alonso, Alicia ;

Izzo, Franco ;

Park, Jane ;

Rozenblatt-Rosen, Orit ;

Regev, Aviv ;

Suva, Mario L. ;

Landau, Dan A. .

NATURE GENETICS, 2021, 53 (10) :1469-+

[9] Aggregate analysis based on TCGA: TTN missense mutation correlates with favorable prognosis in lung squamous cell carcinoma [J].

Cheng, Xingyu ;

Yin, Han ;

Fu, Juan ;

Chen, Chunya ;

An, Jianhong ;

Guan, Jiexia ;

Duan, Rong ;

Li, Hengming ;

Shen, Hong .

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 2019, 145 (04) :1027-1035

[10] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

← 1 2 3 4 5 →