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

• DOI: 10.1016/j.celrep.2017.11.052
• Publication Date: 2017-12-12T13:57:38Z
• Authors: Julien Faget; Svenja Groeneveld; Gael Boivin; Martial Sankar; Nadine Zangger; Miguel Garcia; Nicolas Guex; Inti Zlobec; Loïc Steiner; Alessandra Piersi...; Ioannis Xenarios; Etienne Meylan
• Keywords: CXCL2; MegaClust; PD1; Snail; hypoxia; immune exclusion; immunotherapy; lung cancer; neutrophil; vascularization; Lung Neoplasms; QH301-705.5; Neutrophils; [SDV]Life Sciences [q-bio]; Chemokine CXCL2; Programmed Cell Death 1 Receptor; 610 Medicine & health; Adenocarcinoma of Lung; Adenocarcinoma; Proto-Oncogene Proteins p21(ras); Mice; 03 medical and health sciences; vascularization; immune exclusion; MegaClust; Animals; Antigens, Ly; Humans; Biology (General); Mice, Knockout; 0303 health sciences; Neovascularization, Pathologic; hypoxia; Gene Expression Profiling; neutrophil; Antibodies, Monoclonal; Sciences bio-médicales et agricoles; CXCL2; Prognosis; 3. Good health; [SDV] Life Sciences [q-bio]; PD1; Gene Expression Regulation, Neoplastic; lung cancer; Disease Models, Animal; Snail; Disease Progression; 570 Life sciences; biology; immunotherapy; Leukocyte Reduction Procedures

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.