Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy
Sunay, Melek ME
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The tumor microenvironment is established and maintained through the complex interactions of tumor cells with host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of Sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine. In vitro, Sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Western blot analysis revealed that Sorafenib interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, but not HER-2 or Akt signaling. It also decreased D-type cyclin expression. In vivo, single agent Sorafenib disrupted the tumor-associated vasculature and induced tumor apoptosis, effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that tumor rejection was mediated by both CD4+ and CD8+ T cells. Sorafenib treatment enhanced tumor clearance induced by vaccination with a GM-CSF-secreting, HER-2-expressing cellular vaccine in tumor-bearing FVB/N mice relative to either drug treatment or vaccination alone. Although the magnitude of the peripheral antigen-specific T cell response was unchanged, Sorafenib appeared to enhance antigen-specific T cell accumulation at the tumor site. Overall, these findings suggest that dendritic cell-based immunotherapy can be integrated with Sorafenib, resulting in enhanced therapeutic response.