Adenomatous Polyps Are Driven by Microbe-Instigated Focal Inflammation and Are Controlled by IL-10-Producing T Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-10, Vol.73 (19), p.5905-5913
• Main Authors: DENNIS, Kristen L, YUNWEI WANG, CHANG, Eugene B, KHAZAIE, Khashayarsha, BLATNER, Nichole R, SHUYA WANG, SAADALLA, Abdulrahman, TRUDEAU, Erin, ROERS, Axel, WEAVER, Casey T, LEE, James J, GILBERT, Jack A
• Format: Article
• Language: English
• Subjects: Adenomatous Polyps - etiology; Adenomatous Polyps - pathology; Adoptive Transfer; Animals; Anti-Bacterial Agents - pharmacology; Antineoplastic agents; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Colon - immunology; Colon - metabolism; Colon - pathology; Colonic Neoplasms - complications; Colonic Neoplasms - immunology; Colonic Neoplasms - microbiology; Cytokines - metabolism; Disease Models, Animal; DNA, Bacterial - genetics; Fluorescent Antibody Technique; Immune Tolerance; Inflammation - etiology; Inflammation - pathology; Interleukin-10 - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota - immunology; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; T-Lymphocytes, Regulatory - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-1511

Interleukin (IL)-10 is elevated in cancer and is thought to contribute to immune tolerance and tumor growth. Defying these expectations, the adoptive transfer of IL-10-expressing T cells to mice with polyposis attenuates microbial-induced inflammation and suppresses polyposis. To gain better insights into how IL-10 impacts polyposis, we genetically ablated IL-10 in T cells in APC(Δ468) mice and compared the effects of treatment with broad-spectrum antibiotics. We found that T cells and regulatory T cells (Treg) were a major cellular source of IL-10 in both the healthy and polyp-bearing colon. Notably, T cell-specific ablation of IL-10 produced pathologies that were identical to mice with a systemic deficiency in IL-10, in both cases increasing the numbers and growth of colon polyps. Eosinophils were found to densely infiltrate colon polyps, which were enriched similarly for microbiota associated previously with colon cancer. In mice receiving broad-spectrum antibiotics, we observed reductions in microbiota, inflammation, and polyposis. Together, our findings establish that colon polyposis is driven by high densities of microbes that accumulate within polyps and trigger local inflammatory responses. Inflammation, local microbe densities, and polyp growth are suppressed by IL-10 derived specifically from T cells and Tregs.