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

Caroline Spenlé (1) , Thomas Loustau (1) , Devadarssen Murdamoothoo (1) , William Erne (1) , Stéphanie Beghelli-de La Forest Divonne (2) , Romain Veber (3) , Luciana Petti (4) , Pierre Bourdely (4) , Matthias Mörgelin , Eva Maria Brauchle (5) , Gérard Crémel (1) , Vony Randrianarisoa (1) , Abdouramane Camara (3) , Samah Rekima (2) , Sebastian Schaub (2) , Kelly Nouhen (2) , Thomas Imhof (6) , Uwe Hansen , Nicodème Paul (1) , Raphael Carapito (1) , Nicolas Pythoud (7) , Aurélie Hirschler (7) , Christine Carapito (7) , Hélène Dumortier (8) , Christopher Mueller (9) , Manuel Koch (10) , Katja Schenke-Layland , Shigeyuki Kon (11) , Anne Sudaka (2) , Fabienne Anjuère (4) , Ellen van Obberghen-Schilling (2) , Gertraud Orend (1)

1 IRM - Immuno-Rhumatologie Moléculaire
2 IBV - Institut de Biologie Valrose
3 ICT - Immunopathologie et chimie thérapeutique
4 IPMC - Institut de pharmacologie moléculaire et cellulaire
5 University of Tübingen
6 Universität zu Köln = University of Cologne
7 DSA-IPHC - Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires
8 ICT - Immunologie et chimie thérapeutiques
9 IBMC - Institut de biologie moléculaire et cellulaire
10 University of Freiburg [Freiburg]
11 Hokkaido University [Sapporo, Japan]

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.

Domaines: Cancer; Immunité adaptative; Immunité innée

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, 2020, 8 (9), pp.1122-1138. ⟨10.1158/2326-6066.CIR-20-0074⟩. ⟨hal-02902040⟩