Establishing the Role of Vitamin D signalling in Immunity and Melanoma Specific Survival

1α,25-dihydroxyvitamin D3 signals via its canonical nuclear receptor: Vitamin D
Receptor (VDR). While higher levels of serum vitamin D have been reported to be
associated with thinner primary melanomas and better outcome, increased VDR
expression has been associated with decreased tumour progression and improved
prognosis in melanoma primaries. However, the genomic basis of this effect remains to
be explored and a causal mechanism is yet to be established. To address this question,
I have used microarray data from a cohort of 703 treatment-naïve primary melanomas
from the Leeds Melanoma Cohort (LMC) and corresponding clinical data.
In the LMC primary melanomas, serum vitamin D was not significantly associated
with melanoma survival. However, tumour VDR expression was significantly (and
independently) protective for melanoma death in both the LMC and the TCGA
metastatic melanoma datasets. Tumour VDR expression was found to be significantly
positively correlated with genes enriched for ECM organization, TNF signalling, IFNg
signalling, IL12-mediated signalling and NFkB signalling, which are predominantly
immune-related. Concordantly, VDR expression was lower in tumours graded by the
pathologist as having no immune infiltrate, compared to tumours with brisk and nonbrisk
immune infiltrate. Additionally, VDR correlated positively with imputed immune
cells scores. Conversely, the negatively correlated genes were enriched for Mitotic
Prophase, Wnt signalling pathway, Mitochondrial translation, citric acid cycle and
oxidative phosphorylation, which are predominantly proliferation-related. Of particular
interest among the negatively correlated pathways was the Wnt/b-catenin signalling
pathway. Functional validation using an in vivo tail-vein metastasis assay revealed that
murine melanoma cells stably expressing VDR produced significantly fewer pulmonary
metastases compared to control cells with null VDR expression. VDR-expressing cells
also had significantly lower expression of Wnt/b-catenin signalling genes compared to
control cells. These findings indicate that vitamin D-VDR signalling contributes to
control of pro-proliferative and immunosuppressive Wnt/b-catenin signalling in
melanoma and that this is associated with less proliferative, less metastatic disease
and stronger host immune responses.