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Published on: June 16, 2018
Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer
Julien Faget1, Svenja Groeneveld1, Gael Boivin2
1Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
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.
Insights
Tumor-infiltrating neutrophils (Gr1+ cells) promote lung cancer growth and hinder anti-PD1 immunotherapy by creating a hypoxic microenvironment. This creates a detrimental cycle involving neutrophils and Snail, impacting cancer progression.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Tumor immune microenvironment characterization is crucial for novel cancer therapy development.
- Neutrophils represent a significant component of the tumor immune infiltrate.
- Understanding neutrophil roles in lung cancer is essential for therapeutic strategies.
Purpose of the Study:
- To investigate the role of Gr1+ neutrophils in Kras(G12D)-driven lung cancer progression.
- To elucidate the mechanisms by which neutrophils impact anti-PD1 immunotherapy efficacy.
- To identify key molecular interactions within the tumor microenvironment.
Main Methods:
- Utilized a Kras(G12D)-driven mouse model of lung cancer.
- Performed Gr1+ cell depletion experiments.
- Analyzed T cell homing, angiogenesis, hypoxia, and gene expression (Snail, Cxcl2).
Main Results:
- Gr1+ neutrophils were found to promote tumor growth and impede anti-PD1 immunotherapy.
- Neutrophils altered angiogenesis, induced hypoxia, and sustained Snail expression in cancer cells.
- A positive feedback loop was identified where Snail-expressing cells increase Cxcl2 secretion, further recruiting neutrophils.
Conclusions:
- Gr1+ neutrophils play a critical role in promoting lung cancer progression and resistance to immunotherapy.
- A Snail-neutrophil feedback loop sustains a pro-tumorigenic microenvironment.
- Targeting this neutrophil-Snail axis may offer a novel therapeutic strategy for lung cancer.
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