Enhancement of Dendritic Cell-Based Immunotherapy Using a Small Molecule TGF-beta Receptor Type I Kinase Inhibitor

摘要

Dendritic cells (DC) have become particularly attractive candidates for cancer immunotherapy due to their potent ability to stimulate antigen specific T cells responses. To date DC-based immunotherapy has demonstrated only limited clinical success in the treatment of established tumors. The limited clinical efficacy of existing DC-based cancer vaccines has been attributed in part to suppressive factors produced by the growing tumor, such as transforming growth factor-beta (TGF-beta) that has been shown to impair the immunostimulatory capacity of DCs. Therefore, strategies to neutralize the deleterious effects of TGF-beta may lead to more effective DCbased cancer therapies. SM16 is a potent small molecule TGF-beta receptor type I (TbetaRI) kinase inhibitor that binds to the ATP-binding pocket of this receptor. Here we show that SM16 inhibits the growth and metastasis of established 4T1 mammary tumors when delivered either via daily i.p. injection or orally through rodent chow. Our data indicate that the anti-tumor effects of oral SM16 were superior to those induced by i.p. injection. In addition, we demonstrate that the anti- tumor efficacy of SM16 is dependent on cellular immunity. DC vaccination failed to improve the efficacy of i.p. SM16, but DC vaccines combined with orally administered SM16 increased primary tumor regression. Furthermore, DC+SM16 therapy enhanced T-cell infiltration into the primary tumor and splenocytes isolated from mice on the combination therapy displayed enhanced IFN-gamma production and anti-tumor CTL activity.