Vitamin D–VDR Signaling Inhibits Wnt/β-Catenin–Mediated Melanoma Progression and Promotes Antitumor Immunity

Abstract

1a,25-Dihydroxyvitamin D3 signals via the vitamin D receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As patients with melanoma commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signaling and replicated the findings in The Cancer Genome Atlas metastases. VDR expression was independently protective for melanoma-related death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating antitumor immunity and corresponding with higher imputed immune cell scores and histologically detected tumor-infiltrating lymphocytes. High VDR-expressing tumors had downregulation of proliferative pathways, notably Wnt/b-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (<25 nmol/L $ 10 ng/mL) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/b-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail-vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppressive Wnt/ b-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of a causal relationship between vitamin D-VDR signaling and melanoma survival, which should be explored as a therapeutic target in primary resistance to checkpoint blockade.Significance: VDR expression could potentially be used as a biomarker to stratify patients with melanoma that may respond better to immunotherapy.

Vitamin D receptor(s): In the nucleus but also at membranes?

“…[86,91] Stimulation also shown to be dependent on the PDIA3 membrane complex. [61] In contrast, VDR is implicated in vitamin D-triggered downstream regulation of transcriptional activity of WNT, [92][93][94][95] sonic hedgehog signalling molecule (SHH) [96][97][98][99][100][101] and NOTCH [102][103][104] signalling pathways [95] (Figure 2 Another import argument that PDIA3 is involved in vitamin D signalling came from animal knockout studies. Although an ubiquitous Pdia3 deletion in mice is embryonically lethal, [68,75] heterozygous Pdia3 +/knockout mice showed abnormalities in skeletal tissues [68] indicating effects on calcium homeostasis.…”

Vitamin D and Ovarian Cancer: Systematic Review of the Literature with a Focus on Molecular Mechanisms

“…It has recently been shown that tumour intrinsic Wnt/β-catenin signaling mediates immune exclusion in melanoma and this has been confirmed across other human cancers [63,64]. Vitamin D-VDR signaling inhibits the Wnt/β-catenin pathway and could be explored therapeutically with the aim of counteracting resistance to immunotherapy [63,64].…”

“…On the other hand, pre-existing antitumour T-cell response is associated with a greater efficacy of immune checkpoint blockade, whereas the so-called immune deserted tumours hardly ever respond to immunotherapy [62]. It has recently been shown that tumour intrinsic Wnt/β-catenin signaling mediates immune exclusion in melanoma and this has been confirmed across other human cancers [63,64]. Vitamin D-VDR signaling inhibits the Wnt/β-catenin pathway and could be explored therapeutically with the aim of counteracting resistance to immunotherapy [63,64].…”

The Wnt Signalling Pathway: A Tailored Target in Cancer

“…Low 1α,25-dihydroxyvitamin D3 and vitamin D receptor ( VDR ) level correlates to increased cancer incidence and melanoma progression, respectively. Recently, it has been shown that high VDR expression correlated with the inhibition of tumour growth, low Wnt/β-catenin activation and the induction of the immune response [ 54 ] ( Table 1 ).…”