Reticular fibroblasts counteract radiotherapy-induced head and neck tumor regression through Tenascin-C
Head and neck squamous cell carcinoma (HNSCC) patients have a very short survival. To improve patient survival, there is an emerging need for a better understanding of the obstacles of ionizing irradiation (IR), besides surgery, currently the best treatment option for HNSCC. A confounding factor is the immune suppressive tumor microenvironment (IS-TME) which is orchestrated by tenascin-C (TNC), a highly abundant extracellular matrix (ECM) molecule, getting upregulated by IR. Here, we investigated the roles of TNC on IR-induced tumor regression in a murine oral squamous cell carcinoma (OSCC) model expressing or lacking TNC. While tumors in a TNC-expressing host were radiosensitive, tumors in the TNC genetically-depleted mice were radioresistant pointing at a so far underexplored function of TNC in promoting anti-tumor defense. Upon IR, fibroblast reticular cells (FRCs), a known source of TNC, were more numerous and promoted the IS-TME only in the TNC-expressing tumors. We applied IR to FRCs isolated from lymph nodes and observed that whereas TNC-expressing FRCs were radiosensitive, the TNC-depleted FRCs were radioresistant mimicking the tumor phenotype. Irradiation enhanced the crosstalk of TNC-expressing FRCs with the OSCC causing enhanced tumor cell death but also tumor-promoting plasticity in the survivors as well as induction of Rad51, indicative of enhanced double strand DNA break repair and radioresistance. On the other hand, IR also increased TNC and CCL21 expression in the cocultured FRCs, enforcing an IS-TME. These results demonstrate that TNC determines the FRC tumor promoting phenotype counteracting IR-induced tumor regression, which is relevant in human cancer as a high FRC signature in conjunction with high TNC levels correlates with shorter survival in the irradiated HNSCC patients. We propose that tumor FRCs highly expressing TNC may be an excellent novel target to improve radiotherapy-induced tumor eradication.