ABSTRACT
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with 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 in favor of Bacteroides fragilis, which positively regulates cancer immunity. 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.
Subject(s)
Bacteroides fragilis , Gastrointestinal Microbiome , Immune Checkpoint Inhibitors , Neoplasms , Vitamin D , Animals , Female , Humans , Male , Mice , Bacteroides fragilis/metabolism , Gastrointestinal Microbiome/drug effects , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/metabolism , Mice, Inbred C57BL , Neoplasms/immunology , Neoplasms/microbiology , Neoplasms/therapy , Vitamin D/administration & dosage , Vitamin D/metabolism , Diet , Cell Line, Tumor , Calcifediol/administration & dosage , Calcifediol/metabolism , Vitamin D-Binding Protein/genetics , Vitamin D-Binding Protein/metabolismABSTRACT
Objectives Socioeconomic disparities in pregnancy outcomes have been found across times and places, but there is a lack of studies investigating the underlying causes. The present study investigated the influence of child protective services in the pregnant woman's family of origin as a proxy of childhood social disadvantage. Methods The study population comprised all registered pregnancies in Denmark during the period from 2000 to 2009 that resulted in an induced abortion, spontaneous abortion, stillbirth or live birth (N = 786,054). Linear regression was used to analyze the associations between educational attainment and pregnancy outcomes in models with and without adjustment for age, parental educational attainment and child protective services in the family of origin. Further, it was tested whether child protective services in the pregnant woman's family of origin modified the associations between educational attainment and pregnancy outcomes. Results Women with low educational attainment had a higher risk of induced abortion, stillbirth and preterm delivery and a lower risk of spontaneous abortion. These associations were to some extent explained by child protective services in the family of origin. Further, child protective services in the pregnant woman's family of origin modified the association between educational attainment and risk of preterm delivery. Thus, women with high educational attainment were not found to differ in risk of preterm delivery according to child protective services in the family of origin Conclusions for Practice Information on childhood social disadvantage may enrich our understanding of the socioeconomic disparities in pregnancy outcomes.
