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Tenascin-C orchestrates an immune suppressive tumor microenvironment in oral squamous cell carcinoma

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.
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https://hal.archives-ouvertes.fr/hal-02902040
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Submitted on : Friday, October 9, 2020 - 11:19:37 AM
Last modification on : Wednesday, October 14, 2020 - 4:21:01 AM

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Caroline Spenlé, Thomas Loustau, Devadarssen Murdamoothoo, William Erne, Stéphanie Beghelli-de la Forest Divonne, et al.. Tenascin-C orchestrates an immune suppressive tumor microenvironment in oral squamous cell carcinoma. Cancer Immunology Research, American Association for Cancer Research, 2020, 8 (9), pp.1122-1138. ⟨10.1158/2326-6066.CIR-20-0074⟩. ⟨hal-02902040⟩

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