The local microenvironment drives activation of neutrophils in human brain tumors

Roeltje R Maas¹, Klara Soukup², Nadine Fournier³, Matteo Massara⁴, Sabine Galland⁵, Mara Kornete², Vladimir Wischnewski⁴, Joao Lourenco⁶, Davide Croci², Ángel F Álvarez-Prado⁴, Damien N Marie², Johanna Lilja², Rachel Marcone⁶, Gabriel F Calvo⁷, Rui Santalla Mendez⁴, Pauline Aubel⁴, Leire Bejarano⁴, Pratyaksha Wirapati⁸, Iván Ballesteros⁹, Andrés Hidalgo¹⁰, Andreas F Hottinger¹¹, Jean-Philippe Brouland¹², Roy T Daniel¹³, Monika E Hegi¹⁴, Johanna A Joyce¹⁵

Affiliations

¹ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
² Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland.
³ Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland.
⁴ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
⁵ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
⁶ Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland.
⁷ Department of Mathematics & MOLAB-Mathematical Oncology Laboratory, University of Castilla-La Mancha, Ciudad Real 13071, Spain.
⁸ Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland.
⁹ Program of Cardiovascular Regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain.
¹⁰ Program of Cardiovascular Regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain; Vascular Biology and Therapeutics Program and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
¹¹ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
¹² Department of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne 1011, Switzerland.
¹³ L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
¹⁴ L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
¹⁵ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland. Electronic address: johanna.joyce@unil.ch.

PMID: 37769657
DOI: 10.1016/j.cell.2023.08.043

Free article

The local microenvironment drives activation of neutrophils in human brain tumors

Roeltje R Maas et al. Cell. 2023.

Free article

. 2023 Oct 12;186(21):4546-4566.e27.

doi: 10.1016/j.cell.2023.08.043. Epub 2023 Sep 27.

Authors

Affiliations

¹ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
² Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland.
³ Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland.
⁴ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
⁵ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
⁶ Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland.
⁷ Department of Mathematics & MOLAB-Mathematical Oncology Laboratory, University of Castilla-La Mancha, Ciudad Real 13071, Spain.
⁸ Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne 1011, Switzerland.
⁹ Program of Cardiovascular Regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain.
¹⁰ Program of Cardiovascular Regeneration, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain; Vascular Biology and Therapeutics Program and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
¹¹ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
¹² Department of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne 1011, Switzerland.
¹³ L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
¹⁴ L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
¹⁵ Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne 1011, Switzerland; Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland; L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland. Electronic address: johanna.joyce@unil.ch.

PMID: 37769657
DOI: 10.1016/j.cell.2023.08.043

Abstract

Neutrophils are abundant immune cells in the circulation and frequently infiltrate tumors in substantial numbers. However, their precise functions in different cancer types remain incompletely understood, including in the brain microenvironment. We therefore investigated neutrophils in tumor tissue of glioma and brain metastasis patients, with matched peripheral blood, and herein describe the first in-depth analysis of neutrophil phenotypes and functions in these tissues. Orthogonal profiling strategies in humans and mice revealed that brain tumor-associated neutrophils (TANs) differ significantly from blood neutrophils and have a prolonged lifespan and immune-suppressive and pro-angiogenic capacity. TANs exhibit a distinct inflammatory signature, driven by a combination of soluble inflammatory mediators including tumor necrosis factor alpha (TNF-ɑ) and Ceruloplasmin, which is more pronounced in TANs from brain metastasis versus glioma. Myeloid cells, including tumor-associated macrophages, emerge at the core of this network of pro-inflammatory mediators, supporting the concept of a critical myeloid niche regulating overall immune suppression in human brain tumors.

Keywords: TNF-alpha; angiogenesis; brain metastasis; glioblastoma; glioma; immune suppression; myeloid niche; neutrophil-to-lymphocyte ratio; tumor immune microenvironment; tumor immunology; tumor microenvironment.

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Conflict of interest statement

Declaration of interests D.C. has received consulting fees from Seed Biosciences S.A.; P.W. has provided consulting for Almax, Bayer, Sanofi, and Genentech. A.H. is a paid consultor for Flagship Pioneering, Inc. for matters unrelated to this study; M.E.H. has an advisory role at TME Pharma; J.A.J. received an honorarium for speaking at a Bristol Meyers Squibb research symposium and previously served on the scientific advisory board of Pionyr Immunotherapeutics.

Comment in

Et tu neutrophils? The brain reprograms neutrophils to facilitate tumor progression.
Ross JL, Hambardzumyan D. Ross JL, et al. Immunity. 2023 Nov 14;56(11):2469-2471. doi: 10.1016/j.immuni.2023.10.006. Immunity. 2023. PMID: 37967529

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The local microenvironment drives activation of neutrophils in human brain tumors

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The local microenvironment drives activation of neutrophils in human brain tumors

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