Roles for Inflammation and Regulatory T Cells in Colon Cancer

Risk for developing cancer rises substantially as a result of poorly regulated inflammatory responses to pathogenic bacterial infections. Anti-inflammatory CD4(+) regulatory cells (T-REG) function to restore immune homeostasis during chronic inflammatory disorders. It seems logical that T-REG cells would function to reduce risk of inflammation-associated cancer in the bowel by down-regulating inflammation. It is widely believed, however, that T-REG function in cancer mainly to suppress protective anticancer inflammatory responses. Thus roles for inflammation. T-REG cells, and gut bacteria in cancer are paradoxical and are the subjective of controversy. Our accumulated data build upon the "hygiene hypothesis" model in which gastrointestinal (GI) infections lead to changes in T-REG that reduce inflammation-associated diseases. Ability of T-REG to inhibit or suppress cancer depends upon gut bacteria and IL-10, which serve to maintain immune balance and a protective anti-inflammatory T-REG phenotype. However, under poorly regulated pro-inflammatory conditions. T-REG fail to inhibit and may instead contribute to a T helper (Th)-17-driven procarcinogenic process, a cancer state that is reversible by down-regulation of inflammation and interleukin (IL)-6. Consequently, hygienic individuals with a weakened IL-10- and T-REG-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated inflammation and show more frequent inflammation-associated cancers. Taken together, these data help explain the paradox of inflammation and T-REG in cancer and indicate that targeted stimulation of T-REG may promote health and significantly reduce risk of cancer.