TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma

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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ–induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1) ⁺CD8 ⁺ T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti–PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.

Abstract

TREM2 inhibition remodels myeloid cells in the glioblastoma microenvironment into a proinflammatory state, curbing tumor growth.

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Most cited references 80

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Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

Roger Stupp, Monika E Hegi, Warren P Mason … (2009)

In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

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An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

Cyril Neftel, Julie M.J. Laffy, Mariella G Filbin … (2019)

Diverse genetic, epigenetic and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the TCGA, functional approaches and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4 , EGFR and PDGFRA loci, and by mutations in the NF1 locus, that each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity and their modulation by genetic drivers.

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The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

Scott T. Smith, Rachid El Fatimy, Ron Cialic … (2017)

Microglia play a pivotal role in maintenance of brain homeostasis, but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Alzheimer’s disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ) -plaques in human AD brains. The APOE pathway mediated a switch from a homeostatic to neurodegenerative microglia phenotype following phagocytosis of apoptotic neurons. Triggering receptor expressed on myeloid cells 2 (TREM2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia led to a loss in their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia. Microglia change their phenotype and function during aging and neurodegeneration, but the underlying molecular mechanisms for this change remain unknown. Krasemann, Madore, et al. identify the TREM2-APOE pathway as a major regulator of microglia phenotypic change in neurodegenerative diseases, which may serve as a target to restore homeostatic microglia.

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Author and article information

Contributors

Rui Sun:

ORCID: https://orcid.org/0000-0003-4054-1365

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Rowland Han:

ORCID: https://orcid.org/0000-0002-8615-8532

Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing - review & editing

Colin McCornack:

ORCID: https://orcid.org/0000-0002-7781-1456

Role: Formal analysisRole: SoftwareRole: Visualization

Saad Khan:

ORCID: https://orcid.org/0000-0002-1385-2056

Role: Data curationRole: Formal analysisRole: SoftwareRole: Visualization

G. Travis Tabor:

ORCID: https://orcid.org/0000-0001-9640-3602

Role: MethodologyRole: Resources

Yun Chen:

ORCID: https://orcid.org/0000-0003-0547-9463

Role: InvestigationRole: Resources

Jinchao Hou: Role: InvestigationRole: MethodologyRole: Resources

Haowu Jiang:

ORCID: https://orcid.org/0000-0003-2477-5970

Role: MethodologyRole: Resources

Kathleen M. Schoch: Role: MethodologyRole: Writing - review & editing

Diane D. Mao: Role: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Validation

Ryan Cleary:

ORCID: https://orcid.org/0000-0002-2018-3559

Role: InvestigationRole: Methodology

Alicia Yang: Role: InvestigationRole: MethodologyRole: Validation

Qin Liu:

ORCID: https://orcid.org/0000-0002-1589-0881

Role: ResourcesRole: Writing - review & editing

Jingqin Luo:

ORCID: https://orcid.org/0000-0003-2759-3072

Role: Formal analysisRole: VisualizationRole: Writing - review & editing

Allegra Petti:

ORCID: https://orcid.org/0000-0001-6884-6107

Role: Data curationRole: Formal analysisRole: Project administrationRole: ResourcesRole: SoftwareRole: Visualization

Timothy M. Miller:

ORCID: https://orcid.org/0000-0002-3424-5511

Role: MethodologyRole: ResourcesRole: Writing - review & editing

Jason D. Ulrich:

ORCID: https://orcid.org/0000-0002-4743-926X

Role: Data curationRole: Formal analysisRole: Visualization

David M. Holtzman:

ORCID: https://orcid.org/0000-0002-3400-0856

Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Writing - review & editing

Albert H. Kim:

ORCID: https://orcid.org/0000-0002-1751-8493

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: May 2023

Publication date (Electronic, pub): 12 May 2023

Volume: 9

Issue: 19

Electronic Location Identifier: eade3559

Affiliations

[ ¹ ]Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.

[ ² ]Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.

[ ³ ]Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

[ ⁴ ]Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.

[ ⁵ ]Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA.

[ ⁶ ]Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.

[ ⁷ ]Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.

[ ⁸ ]Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.

[ ⁹ ]The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

[ ¹⁰ ]Center for Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO, USA.

[ ¹¹ ]Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.

Author notes

[* ]Corresponding author. Email: alberthkim@ 123456wustl.edu

Author information

Rui Sun https://orcid.org/0000-0003-4054-1365

Rowland Han https://orcid.org/0000-0002-8615-8532

Colin McCornack https://orcid.org/0000-0002-7781-1456

Saad Khan https://orcid.org/0000-0002-1385-2056

G. Travis Tabor https://orcid.org/0000-0001-9640-3602

Yun Chen https://orcid.org/0000-0003-0547-9463

Haowu Jiang https://orcid.org/0000-0003-2477-5970

Ryan Cleary https://orcid.org/0000-0002-2018-3559

Qin Liu https://orcid.org/0000-0002-1589-0881

Jingqin Luo https://orcid.org/0000-0003-2759-3072

Allegra Petti https://orcid.org/0000-0001-6884-6107

Timothy M. Miller https://orcid.org/0000-0002-3424-5511

Jason D. Ulrich https://orcid.org/0000-0002-4743-926X

David M. Holtzman https://orcid.org/0000-0002-3400-0856

Albert H. Kim https://orcid.org/0000-0002-1751-8493

Article

Publisher ID: ade3559

DOI: 10.1126/sciadv.ade3559

PMC ID: 10181199

PubMed ID: 37172094

SO-VID: c061c1f7-02a6-402f-b926-71ac1eae0dbf

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 10 August 2022

Date accepted : 07 April 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100014571, Alvin J. Siteman Cancer Center;

Award ID: Siteman Investment Program

Funded by: NIH;

Award ID: R01 NS106612

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Copyeditor Jeanelle Ebreo

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TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma

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Most cited references 80

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

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