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Unifying roles for regulatory T cells and inflammation in cancer
Author(s) -
Erdman Susan E.,
Rao Varada P.,
Olipitz Werner,
Taylor Christie L.,
Jackson Erin A.,
Levkovich Tatiana,
Lee ChungWei,
Horwitz Bruce H.,
Fox James G.,
Ge Zhongming,
Poutahidis Theofilos
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24923
Subject(s) - inflammation , immune system , cancer , immunology , proinflammatory cytokine , autoimmunity , medicine , cancer research , biology
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.