Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity

Abstract

The tumor microenvironment (TME) contains high levels of the Wnt family of ligands, and aberrant Wnt-signaling occurs in many tumors. Past studies have been directed toward how the Wnt signaling cascade regulates cancer development, progression and metastasis. However, its effects on host antitumor immunity remain unknown. In this report, we show that Wnts in the TME condition dendritic cells (DCs) to a regulatory state and suppress host antitumor immunity. DC-specific deletion of Wnt co-receptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in mice markedly delayed tumor growth and enhanced host antitumor immunity. Mechanistically, loss of LRP5/6-mediated signaling in DCs resulted in enhanced effector T cell differentiation and decreased regulatory T cell differentiation. This was due to increased production of pro-inflammatory cytokines and decreased production of IL-10, TGF-β1 and retinoic acid (RA). Likewise, pharmacological inhibition of the Wnts' interaction with its cognate co-receptors LRP5/6 and Frizzled (Fzd) receptors had similar effects on tumor growth and effector T cell responses. Moreover, blocking Wnt-signaling in DCs resulted in enhanced capture of tumor-associated antigens and efficient cross-priming of CD8 T cells. Hence, blocking the Wnt pathway represents a potential therapeutic to overcome tumor-mediated immune suppression and augment antitumor immunity.

Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer

“…The role of Wnt/β-catenin signaling in immune cells in the TME and its effect on host antitumor immunity and tumor-induced immune tolerance remain unknown. Recent studies from several labs have shown that increased levels of Wnts in the TME can initiate paracrine signaling and modulate host antitumor immunity (63, 71–75). …”

“…Mechanistically, this is also due to activation of β-catenin signaling in TME DCs and their ability to up regulate immune-regulatory factors such as IDO, IL-10, and Raldh (63, 71, 73, 75). Furthermore, TME DCs express high levels of IL-10 and TGF-β that promotes immune tolerance through induction of IL-10-producing CD4 + and CD8 + T cells (63).…”

“…Furthermore, TME DCs express high levels of IL-10 and TGF-β that promotes immune tolerance through induction of IL-10-producing CD4 + and CD8 + T cells (63). Interestingly, IL-10 production by TME DCs is dependent on the β-catenin/TCF4 signaling axis (63, 71, 75, 76) and mTOR/β-catenin signaling pathway (71). These studies further suggest that Wnt-mediated activation of β-catenin in TME DCs is critical for inducing tumor tolerance.…”

“…These studies further suggest that Wnt-mediated activation of β-catenin in TME DCs is critical for inducing tumor tolerance. Accordingly, conditional deletion of β-catenin or LRP5/6 in DCs markedly reduces regulatory T cell responses with increased effector CD8 T cell responses, leading to suppression of tumor growth (63, 75). Furthermore, blocking Wnt interaction with LRP5/6 and Fzd using small molecule inhibitors in tumor-bearing mice showed increased capture of tumor-associated antigen by DCs.…”

“…Our data show that deletion of β-catenin in DCs results in increased activation of DCs in the TME with increased surface expression of costimulatory molecules and decreased expression of co-inhibitory molecules (63). In addition to inducing regulatory T cells, β-catenin activation in DCs can also affect cross-priming of CD8 + T cell responses against tumors (71, 75). Though β-catenin is known to suppress DC activation and cross-priming (77), it remains to be determined whether β-catenin directly regulates DC activation or does so indirectly via RA and IL-10 (63).…”