Unifying roles for regulatory T cells and inflammation in cancer

Activities of CD4(+) regulatory (T-REG) cells restore immune homeostasis during chronic inflammatory disorders. Roles for T-REG cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that T-REG function in cancer mainly to suppress protective anticancer responses. However, we demonstrate here that T-REG cells also function to reduce cancer risk throughout the body by efficiently downregulating inflammation arising from the gastrointestinal (GI) tract. Building on a hygiene hypothesis model in which GI infections lead to changes in T-REG that reduce immune-mediated diseases, here we show that gut bacteria-triggered T-REG may function to inhibit cancer even in extraintestinal sites. Ability of bacteria-stimulated T-REG to suppress cancer depends on interleukin (IL)-10, which serves to maintain immune homeostasis within bowel and support a protective antiinflammatory T-REG phenotype. However, under proinflammatory conditions, T-REG may fail to provide antiinflammatory protection and instead contribute to a T helper (Th)-17-driven procarcinogenic process; a cancer state that is reversible by downregulation of inflammation. Consequently, hygienic individuals with a weakened IL-10 and T-REG-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated IL-6 and IL-17 and show more frequent inflammation-associated cancers. Taken together, these data unify seemingly divergent disease processes such as autoimmunity and cancer and help explain the paradox of T-REG and inflammation in cancer. Enhancing protective T-REG functions may promote healthful longevity and significantly reduce risk of cancer.