IntroductionA common signature across metastatic cancers is evasion of immune surveillance. Emerging cancers are sculpted by neo-Darwinian selection for superior growth and survival but minimal immunogenicity. Subversion of the immune response by metastatic tumours can be achieved through several mechanisms, one of which involves cytolytic T-lymphocyte selected loss of expression or mutation of genes composing the major histocompatibility class I antigen presentation machinery that render tumours invisible to the adaptive immune response termed immune-escape or immune-editing. Fascinating, hitherto unconnected, ethnographic and experimental findings indicate that cannabinoids inhibit the growth and progression of several categories of cancers. However, the mechanisms underlying these observations remain clouded in scientific uncertainty.Methods and resultsHere, we screened a library of cannabinoid compounds and found molecular selectivity amongst specific cannabinoids, where related molecules such as Δ9-tetrahydrocannabinol, cannabidiol, and cannabigerol can reverse the metastatic immune escape phenotype in vitro by inducing major histocompatibility class I cell surface expression in a wide variety of metastatic tumours that subsequently sensitizing tumours to T lymphocyte recognition. Remarkably, H3K27Ac ChIPseq analysis established that cannabigerol and interferon gamma induce overlapping gene signatures and key gene pathways that are activated in cannabigerol-treated metastatic tumours related to cellular senescence and antigen presentation machinery genes involved in revealing metastatic tumours to the adaptive immune response.DiscussionOverall, the data suggest that specific cannabinoids may have utility in cancer immunotherapy regimens by overcoming immune escape and augmenting cancer immune surveillance in metastatic disease. Finally, the discovery of the ability of cannabinoids to alter epigenetics programs may elucidate many of the pleiotropic medicinal effects of cannabinoids on human physiology.

For eons, turmeric and curcumin have been used as culinary spices and as traditional medicines and as vogue dietary supplements for a growing list of disorders, including arthritis, digestive disorders, respiratory infections, allergies, liver disease, depression and cancer. The activities of these spices are commonly attributed to curcuminoids; however, the medical applications of this class of compounds has been limited due to the low water solubility, chemical instability, acid lability, poor absorption, rapid catabolism by enzymes of the diverse curcuminoids contained in turmeric and curcumin extracts. Furthermore, identifying the bio-active curcuminoids with unique molecular entities responsible for specific medicinal benefit is at its infancy. To overcome these many issues and substantially advance this area of inquiry, we created a water-soluble achiral curcuphenol analogue and a water-soluble racemic analogue that have enhanced chemical characteristics and biological performance, and we subsequently demonstrated their ability to reverse the immune-escape phenotype, a process that enables tumours to hide from host immune responses and thereby provides tumours a significant growth advantage to metastatic tumours. The discovery that curcuphenols can reverse tumour immune-escape mechanisms and thereby reduce tumour growth, provides a rationale for the development of advanced dissecting nutraceuticals and bioceuticals for unique chemical entities as therapeutic building blocks to synthesize analogues with optimal chemical characteristics capable of harnessing the power of the immune system to extinguish metastatic cancers and beyond.