Tenascin-C Orchestrates an Immune-Suppressive Tumor Microenvironment in Oral Squamous Cell Carcinoma
- 1 September 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 8 (9), 1122-1138
- https://doi.org/10.1158/2326-6066.cir-20-0074
Abstract
Inherent immune suppression represents a major challenge in the treatment of human cancer. The extracellular matrix molecule tenascin-C promotes cancer by multiple mechanisms, yet the roles of tenascin-C in tumor immunity are incompletely understood. Using a 4NQO-induced oral squamous cell carcinoma (OSCC) model with abundant and absent tenascin-C, we demonstrated that tenascin-C enforced an immune suppressive lymphoid stroma via CCL21/CCR7 signaling, leading to increased metastatic tumors. Through TLR4, tenascin-C increased expression of CCR7 in CD11c+ myeloid cells. By inducing CCL21 in lymphatic endothelial cells via integrin α9β1 and binding to CCL21, tenascin-C immobilized CD11c+ cells in the stroma. Inversion of the lymph node-to-tumor CCL21 gradient, recruitment of T regulatory cells, high expression of anti-inflammatory cytokines and matrisomal components were hallmarks of the tenascin-C-instructed lymphoid stroma. Ablation of tenascin-C or CCR7 blockade inhibited the lymphoid immune suppressive stromal properties, reducing tumor growth, progression and metastasis. Thus, targeting CCR7 could be relevant in human head and neck tumors as high tenascin-C expression and an immune suppressive stroma correlate to poor patient survival.Keywords
Other Versions
Funding Information
- ARC (PAIR-VADS11-023)
- ARC (AAP2017.LNCC/EVO)
- Cancéropôle PACA and LABEX SIGNALIFE (ANR-11-LABEX-0028-01)
- Deutsche Forschungsgemeinschaft (EXC 2180, INST 2388/64-1)
- Ministry of Science, Research and Art Baden-Württemberg (SI-BW 01222-91, 33-729.55-3/214-8)
This publication has 66 references indexed in Scilit:
- Tenascin C Promiscuously Binds Growth Factors via Its Fifth Fibronectin Type III-Like DomainPLOS ONE, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular MatricesMolecular & Cellular Proteomics, 2012
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- Regulation of Antigen-Experienced T Cells: Lessons from the Quintessential Memory Marker CD44Frontiers in Immunology, 2012
- Role of angiogenesis in oral squamous cell carcinoma development and metastasis: an immunohistochemical studyInternational Journal of Oral Science, 2011
- Advances in tenascin-C biologyCellular and Molecular Life Sciences, 2011
- Chemotrap-1: An Engineered Soluble Receptor That Blocks Chemokine-Induced Migration of Metastatic Cancer CellsIn vivoCancer Research, 2010
- Extracellular Matrix of Glioblastoma Inhibits Polarization and Transmigration of T Cells: The Role of Tenascin-C in Immune SuppressionThe Journal of Immunology, 2010
- Collagen VI Is a Subepithelial Adhesive Target for Human Respiratory Tract PathogensJournal of Innate Immunity, 2009