Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer
Open Access
- 1 July 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (7), 3560-3575
- https://doi.org/10.1172/jci124037
Abstract
Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the impact of tumor-infiltrating-lymphocyte subpopulations on lung cancer biology by studying in vitro co-cultures, 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. Co-culturing 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. Co-injection of Th9 and/or Th17 cells with tumor cells in wildtype, 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 for novel therapeutic strategies.Keywords
Funding Information
- .. (........)
This publication has 52 references indexed in Scilit:
- Th17/IL-17A Might Play a Protective Role in Chronic Lymphocytic Leukemia ImmunityPLOS ONE, 2013
- Effector CD4 and CD8 T Cells and Their Role in the Tumor MicroenvironmentCancer Microenvironment, 2012
- IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitisJCI Insight, 2012
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patientsLung Cancer, 2010
- Measuring dementia carers' unmet need for services - an exploratory mixed method studyBMC Health Services Research, 2010
- IL-17 Promotes Tumor Development through the Induction of Tumor Promoting Microenvironments at Tumor Sites and Myeloid-Derived Suppressor CellsThe Journal of Immunology, 2010
- 14-3-3ζ Cooperates with ErbB2 to Promote Ductal Carcinoma In Situ Progression to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal TransitionCancer Cell, 2009
- Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lungLaboratory Investigation, 2009
- Tumor-specific Th17-polarized cells eradicate large established melanomaBlood, 2008