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

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.

• Authors: Julien Faget, Svenja Groeneveld, Gael Boivin, Martial Sankar, Nadine Zangger, Miguel Garcia, Nicolas Guex, Inti Zlobec, Loïc Steiner, Alessandra Piersigilli, Ioannis Xenarios, Etienne Meylan
• Journal: Cell reports (Cell Rep) Vol. 21 Issue 11 Pg. 3190-3204 (Dec 12 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 29241546 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• 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)

Topics

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