Vitamin D regulates microbiome-dependent cancer immunity

Numerous studies have suggested a role for vitamin D in immune modulation and in cancer. The tissue availability of vitamin D and its active metabolites is controlled in part by vitamin D binding protein, formally known as "group-specific component" (Gc) protein. Here, we report that mice lacking Gc, or mice given a diet high in vitamin D, display increased immune-dependent resistance to transplantable cancers and augmented responses to immune checkpoint blockade cancer therapy. Similarly, in humans, a vitamin D-induced gene signature correlates with improved responses to immune checkpoint inhibitor treatment, as well as with signatures of immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition favoring Bacteroides fragilis that positively regulate cancer immunity. Tumor resistance can be transferred in dominant fashion to wild-type animals by coprophagy, fecal transplantation or gavage with Bacteroides fragilis provided dietary intake of vitamin D is not restricted. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.