β-Catenin Promotes Regulatory T-cell Responses in Tumors by Inducing Vitamin A Metabolism in Dendritic Cells

Abstract

Tumors actively suppress antitumor immunity creating formidable barriers to successful cancer immunotherapy. The molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that dendritic cells (DCs) in the tumor microenvironment (TME) acquire the ability to metabolize vitamin A to produce retinoic acid (RA), which drives T regulatory responses and immune tolerance. Tolerogenic responses were dependent on induction of vitamin A-metabolizing enzymes via the β-catenin/T Cell Factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of β-catenin in mice markedly reduced T regulatory responses and delayed melanoma growth. Pharmacological inhibition of either vitamin A metabolizing enzymes or the β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and T regulatory responses. Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy.

Canonical Wnt Signaling in Dendritic Cells Regulates Th1/Th17 Responses and Suppresses Autoimmune Neuroinflammation

“…Previous studies have shown that wnt3a specifically activates β-catenin in DCs (30–32). Consistent with these studies(30–32), the wnt3a treatment of DCs from TCF reporter mice showed an increase in the reporter gene expression compared to untreated DCs (Fig. 4a).…”

“…In models of gut tolerance and tumor-induced immune tolerance, our recent studies have shown that activation of β-catenin in DCs induces T regulatory responses, and suppresses intestinal inflammation and antitumor immunity (19, 32). However, whether this pathway in DCs regulates peripheral immune homeostasis and neuroinflammation is not known.…”

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

“…Loss of b-catenin impairs the ability of DCs to induce Tregs (20), instead the activation of b-catenin pathway increases the capacity of DC to release IL10 and promote immune tolerance, (21,22). In DCs, b-catenin signaling synergizes with other pathways, such as the Erk pathway, to induce anti-inflammatory cytokines and proliferation of Tregs.…”

Tumors induce immune tolerance through activation of β-catenin/TCF4 signaling in dendritic cells: A novel therapeutic target for cancer immunotherapy

“…4 However, it is possible that tumors can induce regulatory DCs by activating b-catenin/ TCF pathway and promote immune suppression. In our recent study, 5 we have put this idea to the test and showed tumors exploit b-catenin/TCF pathway as a potential immune evasion mechanism.…”

“…Consistent with these studies, our data showed that this pathway is active in DCs isolated from tumor draining lymph node (TDLN) and tumor. 5 To further examine the role of this pathway in DC-mediated immune suppression, we have generated mice that selectively lacked b-catenin in DCs (referred to as b-cat DDC mice). DCspecific deletion of b-catenin resulted in delayed melanoma (MO4) and thymoma tumor growth compared with control mice.…”