FoxP3 expressing regulatory T-cells play an important role in the induction of peripheral tolerance and the prevention of auto-immune responses. How the functionality of regulatory T-cells is regulated at the site of inflammation remains poorly understood. We just recently discovered that the functionality of regulatory T-cells is regulated via the EGF-R that is expressed by activated regulatory T-cells. In in vitro suppression assays the presence of the EGF-like growth factor Amphiregulin significantly enhanced the suppressive capacity of regulatory T-cells and, in vivo, Amphiregulin-induced signals enabled regulatory T-cells to induce tolerance against innocuous antigens. This effect was blocked upon application of EGF-R antagonists (Zaiss et al. 2013).Based on these findings, the objectives of this proposal are:1.a) To determine the role of regulatory T-cells during tumor therapy; in specific during induced lymphopenia in the context of adoptive cell transfer (ACT) based tumor therapy.1.b) To determine whether EGF-R inhibitors can suppress regulatory T-cell function such that they enhance the efficacy of ACT based tumor therapy?2) To determine whether smallpox viruses use their virus-encoded EGF-like growth factors to enhance regulatory T-cell function, and thus as an immune escape mechanism? This will answer the question whether interference with regulatory T-cell function explains for the immune-stimulatory effect of EGF-R inhibitor treatment, during vaccinia virus infections.3) To determine whether we can develop an EGF-R inhibitor that selectively targets regulatory T-cells, and thus keeps all other functions of the EGF-R, for example in tissue homeostasis, intact?Taken together, this proposed project tests a novel therapeutic approach by which we expect to have hit a so far unrecognized, therapeutic “Achilles’ heel” of Tregs, i.e. via the regulation of Treg functionality by EGF-R ligands.