Inhibitors of ß-catenin affect the immuno-phenotype and functions of dendritic cells in an inhibitor-specific manner.

ABSTRACT

Many tumors are characterized by mutation-induced constitutive activation of ß-catenin which promotes tumor growth and survival. Consequently, the development of specific ß-catenin inhibitors for tumor therapy has come into the focus of drug development. ß-Catenin was also shown to contribute to the tolerance-promoting function of unstimulated dendritic cells (DCs). In response to activation, DCs acquire potent T cell stimulatory capacity and induce profound tumor antigen-specific immune responses. Here we asked for effects of pre-clinically established ß-catenin inhibitors (CCT-031374, iCRT-5, PNU-75654) on mouse bone marrow-derived (BM)DCs. All three inhibitors moderately increased surface expression of MHCII, CD80, and CD86 on unstimulated DCs, but had no enhancing effect on their capacity to stimulate the proliferation of ovalbumin (OVA) specific CD4(+) T cells. CCT-031374 interfered with upregulation of costimulators (CD40, CD86) and cytokines (IL-1ß, TNF-α, IL-6, IL-10, IL-12) by LPS-stimulated DCs. Accordingly, this DC population displayed an impaired CD4(+) T cell stimulatory activity. iCRT-5 and PNU-75654 had no detrimental effects on the immuno-phenotype of stimulated DCs. Hence, DCs treated with iCRT-5 in the course of stimulation exerted comparably strong T cell proliferation as did control DCs. In contrast, DCs stimulated in the presence of PNU-75654 induced less T cell proliferation than the control population despite enhanced uptake and processing of OVA. Our findings suggest that the differential effects of ß-catenin inhibitors on stimulated DCs reflect off target effects. Concerning potential application of ß-catenin inhibitors for tumor therapy, iCRT-5 may be most beneficial, since it did not exert detrimental effects on stimulated DCs.