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.
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. serdman@mit.edu
Susan E
SE
Erdman
Varada P
VP
Rao
Werner
W
Olipitz
Christie L
CL
Taylor
Erin A
EA
Jackson
Tatiana
T
Levkovich
Chung-Wei
CW
Lee
Bruce H
BH
Horwitz
James G
JG
Fox
Zhongming
Z
Ge
Theofilos
T
Poutahidis
D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D044923:Helicobacter hepaticus / Q000472:pathogenicity; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D016753:Interleukin-10 / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured
D025601:Adenomatous Polyposis Coli Protein; D016207:Cytokines; D004268:DNA-Binding Proteins; D016753:Interleukin-10; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C499308:Rag2 protein, mouse; C524056:Erbb2 protein, mouse