Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer

Julien Faget; Svenja Groeneveld; Gael Boivin; Martial Sankar; Nadine Zangger; Miguel Garcia; Nicolas Guex; Inti Zlobec; Loïc Steiner; Alessandra Piersigilli; Ioannis Xenarios; Etienne Meylan

doi:10.1016/j.celrep.2017.11.052

Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer

Cell Rep. 2017 Dec 12;21(11):3190-3204. doi: 10.1016/j.celrep.2017.11.052.

Authors

Affiliations

¹ Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
² Radiobiology Laboratory, Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
³ Vital-IT, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
⁴ Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
⁵ Flow Cytometry Core Facility, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
⁶ Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
⁷ Institute of Animal Pathology, University of Bern, 3012 Bern, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
⁸ Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: [email protected].

PMID: 29241546
DOI: 10.1016/j.celrep.2017.11.052

Abstract

Understanding the immune compartment of tumors facilitates the development of revolutionary new therapies. We used a Kras(G12D)-driven mouse model of lung cancer to establish an immune signature and identified a contribution of Gr1⁺ neutrophils to disease progression. Depletion experiments showed that Gr1⁺ cells (1) favor tumor growth, (2) reduce T cell homing and prevent successful anti-PD1 immunotherapy, and (3) alter angiogenesis, leading to hypoxia and sustained Snail expression in lung cancer cells. In turn, Snail accelerated disease progression and increased intratumoral Cxcl2 secretion and neutrophil infiltration. Cxcl2 was produced mainly by neutrophils themselves in response to a factor secreted by Snail-expressing tumor cells. We therefore propose a vicious cycle encompassing neutrophils and Snail to maintain a deleterious tumor microenvironment.

Keywords: CXCL2; MegaClust; PD1; Snail; hypoxia; immune exclusion; immunotherapy; lung cancer; neutrophil; vascularization.

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / immunology
Adenocarcinoma / mortality
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Animals
Antibodies, Monoclonal / pharmacology
Antigens, Ly / genetics
Antigens, Ly / immunology
Chemokine CXCL2 / genetics
Chemokine CXCL2 / immunology
Disease Models, Animal
Disease Progression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Leukocyte Reduction Procedures
Lung Neoplasms / genetics*
Lung Neoplasms / immunology
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Mice
Mice, Knockout
Neovascularization, Pathologic / genetics*
Neovascularization, Pathologic / immunology
Neovascularization, Pathologic / mortality
Neovascularization, Pathologic / pathology
Neutrophils / drug effects
Neutrophils / immunology*
Neutrophils / pathology
Prognosis
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology*
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / immunology
Signal Transduction
Snail Family Transcription Factors / genetics
Snail Family Transcription Factors / immunology*
Survival Analysis
Tumor Microenvironment

Substances

Antibodies, Monoclonal
Antigens, Ly
Chemokine CXCL2
Cxcl2 protein, mouse
Ly6G antigen, mouse
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Snai1 protein, mouse
Snail Family Transcription Factors
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)