Tenascin-C orchestrates radiotherapy-induced head and neck tumor regression.

Given that head and neck squamous cell carcinoma (HNSCC) patients have poor survival outcomes, a better understanding of the therapeutic benefits of ionizing irradiation (IR), the major treatment modality besides surgery, is needed. A confounding factor is the immunosuppressive tumor microenvironment determined by tenascin-C (TNC), a highly abundant extracellular matrix molecule upregulated by IR. We investigated the roles of TNC on radio-induced tumor regression in a murine oral HNSCC model expressing or lacking TNC. While tumors in a TNC-expressing host were radiosensitive, they were radioresistant in TNC genetically depleted mice. We identified fibroblast reticular cells (FRCs) as critical regulators. TNC plays a compartmentalized and dual role in regulating tumor radiosensitivity with a detrimental role in the tumor stroma opposed to an essential role in the tumor-draining lymph nodes. This is relevant as a high FRC signature and high TNC levels together correlate with shorter HNSCC patient survival. TNC-expressing FRCs may be an excellent novel target to improve radiotherapy-induced tumor eradication, as our TNC targeting MAREMO peptide reduced tumor cell numbers and plasticity upon IR.