Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer
Ylia Salazar, … , Magdalena Huber, Rajkumar Savai
Ylia Salazar, … , Magdalena Huber, Rajkumar Savai
Published March 31, 2020
Citation Information: J Clin Invest. 2020;130(7):3560-3575. https://doi.org/10.1172/JCI124037.
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Research Article Inflammation Oncology

Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer

Abstract

Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on lung cancer biology by studying in vitro cocultures, in vivo mouse models, and human lung cancer tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17 cells was detected in human lung cancer tissue and correlated with poor survival. Coculturing lung cancer cells with Th9/Th17 cells or exposing them to the respective CM induced EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL-9 and IL-17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Coinjection of Th9/Th17 cells with tumor cells in WT, Rag1–/–, Il9r–/–, and Il17ra–/– mice altered tumor growth and metastasis. Accordingly, inhibition of IL-9 or IL-17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration and metastatic spreading and offering potentially novel therapeutic strategies.

Authors

Ylia Salazar, Xiang Zheng, David Brunn, Hartmann Raifer, Felix Picard, Yajuan Zhang, Hauke Winter, Stefan Guenther, Andreas Weigert, Benno Weigmann, Laure Dumoutier, Jean-Christophe Renauld, Ari Waisman, Anja Schmall, Amanda Tufman, Ludger Fink, Bernhard Brüne, Tobias Bopp, Friedrich Grimminger, Werner Seeger, Soni Savai Pullamsetti, Magdalena Huber, Rajkumar Savai

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Figure 4

Coculture with Th9 or Th17 cells affects tumor cell gene profile.

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Coculture with Th9 or Th17 cells affects tumor cell gene profile. (A) MA...
(A) MA plot of RNA-Seq data showing log2 average signal intensity of treatment groups (y axis) versus log2 average signal intensity of control group (LLC1 + Th0; x axis). Regulated genes are colored based on adjusted P value (FDR) < 0.05 (B) Pathway enrichment analysis in PANTHER database for differentially regulated genes in LLC1 cells cocultured with Th9 or Th17 cells as compared with Th0. (C) Heatmap of differentially expressed genes (Z score normalized) in LLC1 + Th9 and LLC1 + Th17 groups. Genes with higher expression levels are shown in red, while genes with lower expression levels are shown in blue. (D) Heatmap of differentially expressed transcription factors in LLC1 + Th9 and LLC1 + Th17 groups. Z score normalized gene expression is shown for top25 upregulated and downregulated genes based on lowest adjusted P value. Genes with higher expression levels are shown in red, while genes with lower expression levels are shown in blue. n = 3 experimental replicates, clustering of heatmaps by Pearson correlation.