Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis

Background: Transforming growth factor (TGF)-beta is known to be produced by progressor tumors and to immobilize dendritic cells (DCs) within those tumors. Moreover, although TGF-beta 1 has been shown to promote tumor progression, there is still no direct, in vivo evidence as to whether TGF-beta 1 is able to directly induce distant metastasis. Methods: To address that issue and investigate the mechanism by which TGF-beta 1 suppresses DC activity, we subdermally inoculated mouse ears with squamous cell carcinoma cells stably expressing TGF-beta 1 or empty vector (mock). Results: The numbers of DCs within lymph nodes draining the resultant TGF-beta 1-expressing tumors was significantly lower than within nodes draining tumors not expressing TGF-beta 1. We then injected fluorescently labeled bone marrow-derived dendritic cells into the tumors, and subsequent analysis confirmed that the tumors were the source of the DCs within the tumor-draining lymph nodes, and that there were significantly fewer immature DCs within the nodes draining TGF-beta 1-expressing tumors than within nodes draining tumors not expressing TGF-beta 1. In addition, 14 days after tumor cell inoculation, lymph node metastasis occurred more frequently in mice inoculated with TGF-beta 1 transfectants than in those inoculated with the mock transfectants. Conclusions: These findings provide new evidence that tumor-derived TGF-beta 1 inhibits migration of DCs from tumors to their draining lymph nodes, and this immunosuppressive effect of TGF-beta 1 increases the likelihood of metastasis in the affected nodes.