Type 2 innate lymphoid cells (ILC2) potentiate immune responses, however, their role in mediating adaptive immunity in cancer has not been assessed. Here, we report that mice genetically lacking ILC2s have significantly increased tumour growth rates and conspicuously higher frequency of circulating tumour cells (CTCs) and resulting metastasis to distal organs. Our data support the model that IL-33 dependent tumour-infiltrating ILC2s are mobilized from the lungs and other tissues through chemoattraction to enter tumours, and subsequently mediate tumour immune-surveillance by cooperating with dendritic cells to promote adaptive cytolytic T cell responses. We conclude that ILC2s play a fundamental, yet hitherto undescribed role in enhancing anti-cancer immunity and controlling tumour metastasis.

A new paradigm for understanding immune-surveillance and immune escape in cancer is described here. Metastatic carcinomas express reduced levels of IL-33 and diminished levels of antigen processing machinery (APM), compared to syngeneic primary tumours. Complementation of IL-33 expression in metastatic tumours upregulates APM expression and functionality of major histocompatibility complex (MHC)-molecules, resulting in reduced tumour growth rates and a lower frequency of circulating tumour cells. Parallel studies in humans demonstrate that low tumour expression of IL-33 is an immune biomarker associated with recurrent prostate and kidney renal clear cell carcinomas. Thus, IL-33 has a significant role in cancer immune-surveillance against primary tumours, which is lost during the metastatic transition that actuates immune escape in cancer.

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.