Abstract 5036: Tumor-induced activation of the Wnt/β-catenin/TCF4 pathway in dendritic cells promotes immune tolerance

Abstract

Abstract Tumors actively suppress host antitumor immune response and this represents a fundamental barrier to successful cancer immunotherapy. However, the molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that Wnt ligands in the tumor microenvironment activate the β-catenin/TCF4 pathway within dendritic cells (DCs) rendering them tolerogenic and able to suppress host antitumor immunity against melanoma. This was because Wnt/β-catenin/TCF4 signaling in DCs induced retinoic acid synthesizing enzymes, which induced T regulatory responses and suppressed effector T cells. Consistent with this observation, DC-specific deletion of key downstream mediators of canonical Wnt signaling (Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6), β-catenin and transcription factor 4 (TCF4)) in mice markedly delayed melanoma growth and enhanced host anti-tumor immunity. Likewise, pharmacological inhibition of the Wnt/β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and effector T cell responses. Hence, Wnt/β-catenin/TCF4 pathway links together DCs, Tregs and the retionoic acid pathway, and is an important target for anticancer immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Yuan Hong, Indumathi Manoharan, Amol Suryawanshi, Santhakumar Manicassamy. Tumor-induced activation of the Wnt/β-catenin/TCF4 pathway in dendritic cells promotes immune tolerance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5036. doi:10.1158/1538-7445.AM2015-5036