Cell Reports
Volume 21, Issue 11, 12 December 2017, Pages 3190-3204
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Article
Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer

https://doi.org/10.1016/j.celrep.2017.11.052Get rights and content
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Highlights

  • An unsupervised immune signature allows stratification of poorly immunogenic tumors

  • Neutrophil depletion reverts immune exclusion allowing anti-PD1 treatment efficacy

  • Neutrophils alter angiogenesis, increasing hypoxia and stabilizing Snail

  • Snail favors neutrophil homing, induces partial EMT, and enhances tumor progression

Summary

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

lung cancer
neutrophil
MegaClust
vascularization
hypoxia
immunotherapy
PD1
immune exclusion
Snail
CXCL2

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9

These authors contributed equally

10

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