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

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

Author information

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: etienne.meylan@epfl.ch.

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

PMID:
29241546
DOI:
10.1016/j.celrep.2017.11.052
[Indexed for MEDLINE]
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