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

To address that issue and investigate the mechanism by which TGF-β1 suppresses DC activity, we subdermally inoculated mouse ears with squamous cell carcinoma cells stably expressing TGF-β1 or empty vector (mock).The numbers of DCs within lymph nodes draining the resultant TGF-β1-expressing tumors was significantly lower than within nodes draining tumors not expressing TGF-β1. 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-β1-expressing tumors than within nodes draining tumors not expressing TGF-β1. In addition, 14 days after tumor cell inoculation, lymph node metastasis occurred more frequently in mice inoculated with TGF-β1 transfectants than in those inoculated with the mock transfectants.These findings provide new evidence that tumor-derived TGF-β1 inhibits migration of DCs from tumors to their draining lymph nodes, and this immunosuppressive effect of TGF-β1 increases the likelihood of metastasis in the affected nodes.Transforming growth factor (TGF) -β can reportedly promote cancer metastasis by affecting the tumor microenvironment in a manner that facilitates tumor cell invasion [1,2] and by inhibiting immune cell function [3]. Consistent with those reports, overproduction of TGF-β by tumors is frequently associated with metastasis [4-6] and a poor prognosis in patients with cancer [7-10]. Among the three highly homologous TGF-β isoforms, TGF-β1 is the most abundant and most extensively studied [11]. We previously showed that tumor-derived TGF-β1 causes a reduction in the number of dendritic cells (DCs) within tumor-draining lymph nodes (TDLNs) [12]. It also has been shown that TGF-β1 is produced by progressor tumors and that it immobilizes the DCs within those tumors [13]. This is noteworthy because DCs are highly speci