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Tenascin-C Orchestrates an Immune-Suppressive Tumor Microenvironment in Oral Squamous Cell Carcinoma
Caroline Spenlé1, Thomas Loustau1, Devadarssen Murdamoothoo1
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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.
Insights
Tenascin-C promotes oral cancer immune suppression by creating a lymphoid stroma via CCL21/CCR7 signaling, increasing metastasis. Blocking tenascin-C or CCR7 reduced tumor growth and spread.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immune suppression is a key challenge in cancer treatment.
- Tenascin-C (TNC) is an extracellular matrix molecule implicated in cancer progression.
- The specific role of TNC in tumor immunity remains unclear.
Purpose of the Study:
- To investigate the role of tenascin-C in regulating the tumor immune microenvironment.
- To elucidate the mechanisms by which TNC influences immune suppression in oral squamous cell carcinoma (OSCC).
- To evaluate the therapeutic potential of targeting TNC or CCR7 signaling.
Main Methods:
- Utilized a 4NQO-induced OSCC mouse model with varying TNC levels.
- Analyzed immune cell infiltration and stromal properties.
- Investigated the involvement of CCL21/CCR7 signaling pathway and TLR4.
- Assessed the impact of TNC or CCR7 blockade on tumor progression and metastasis.
Main Results:
- Tenascin-C promoted an immune-suppressive lymphoid stroma via CCL21/CCR7 signaling, enhancing tumor metastasis.
- TNC upregulated CCR7 on CD11c+ myeloid cells through TLR4.
- TNC induced CCL21 in lymphatic endothelial cells, immobilizing myeloid cells and altering the CCL21 gradient.
- TNC-induced stroma showed T regulatory cell recruitment and elevated anti-inflammatory cytokines.
- Ablation of TNC or blockade of CCR7 significantly reduced tumor growth, progression, and metastasis.
Conclusions:
- Tenascin-C orchestrates an immune-suppressive microenvironment in OSCC through the CCL21/CCR7 axis.
- Targeting CCR7 is a potential therapeutic strategy for head and neck cancers.
- High TNC expression and immune-suppressive stroma correlate with poor patient survival in head and neck tumors.
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