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  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.

Tenascin-W Is a Novel Stromal Marker in Biliary Tract Cancers

“…The C-terminal fibrinogen-related domain of tenascin-W, like that of tenascin-C, can activate Toll-like receptor 4-mediated inflammatory responses ( 53 ). Moreover, tenascin-C was recently shown to contribute to immune suppression in an oral squamous cell carcinoma model ( 18 ). Future studies should be directed to determine if tenascin-W, which shares a number of features with tenascin-C, plays a similar role in tumor stroma, or if the presence of tenascin-W during cholelithiasis could contribute to tumor progression.…”

“…In vitro , tenascin-C promotes the proliferation and migration of many tumor-derived cell lines ( 17 ) and there are reduced metastases in tenascin-C knockout mice and in mice lacking factors that promote the expression of tenascin-C ( 16 ). Tenascin-C may also play a role in creating an immune suppressive tumor stroma, thus contributing to tumor growth and metastasis ( 18 ). Tenascin-C has been proposed as a marker, immunotherapy target and indicator of prognosis in many kinds of cancer ( 16 ), but its use has been limited by its presence, albeit at lower levels, in many normal adult tissues ( 19 ).…”

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

“…Similarly, IL-7 and IL-2 bind fibronectin (94), laminin, and collagen IV; while TNF-a (98), which acts on T cells, B cells, monocytes, endothelial cells and fibroblasts binds with FN (110) and laminin (99). Finally, tenascin-C binds to CCL21 enforcing an immune-suppressive lymphoid stroma, as shown in a model of oral squamous cell carcinoma (97). By inducing CCL21 and binding to it, tenascin-C instructed lymphoid stroma to recruit T regulatory cells and express high levels of anti-inflammatory cytokines.…”

Tenascin-W: Discovery, Evolution, and Future Prospects

“…It is typically abundant in solid tumors and can affect cancer cell behavior ( 19 ), but the significance of these observations is still unknown. It is possible that tenascin-W plays a role similar to tenascin-C in the creation of an immune-suppressive environment in tumor stroma ( 25 ), though this hypothesis needs to be tested. The fibrinogen-related domain of tenascin-W, like that of tenascin-C, can bind and activate TLR4, which indicates tenascin-W may play a role in inflammation and inflammatory diseases ( 26 ).…”