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1.
Cancer Immunol Res ; 3(7): 806-14, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25855122

ABSTRACT

IL10 is attributed with immune-suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation, leading to colitis and cancer. Consistent with this, transfer of IL10-competent regulatory T cells (Treg) into mice with colitis or hereditary polyposis protects against disease, while IL10-deficient mice are predisposed to polyposis with increased colon polyp load. Little is known about the protective or pathogenic function of IL10 in cancers of the small intestine. We found CD4(+) T cells and CD4(+) Foxp3(+) Tregs to be the major sources of IL10 in the small intestine and responsible for the increase in IL10 during polyposis in the APC(Δ468) mouse model of hereditary polyposis. Targeted ablation of IL10 in T cells caused severe IL10 deficiency and delayed polyp growth. However, these polyps progressively lost cytotoxic activity and eventually progressed to cancer. Several observations suggested that the effect was due to the loss of IFNγ-dependent immune surveillance. IL10-incompetent CD4(+) T cells failed to secrete IFNγ when stimulated with polyp antigens and were inefficient in T-helper-1 (TH1) commitment. By contrast, the TH17 commitment was unaffected. These findings were validated using mice whose T cells overexpress IL10. In these mice, we observed high intra-polyp cytotoxic activity and attenuation of polyposis. Thus, expression of IL10 by T cells is protective and required for immune surveillance in the small intestine.


Subject(s)
Immunologic Surveillance , Interleukin-10/immunology , Intestinal Neoplasms/immunology , Intestine, Small/pathology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout
2.
Sci Transl Med ; 6(225): 225ra28, 2014 Feb 26.
Article in English | MEDLINE | ID: mdl-24574339

ABSTRACT

The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/ß-catenin signaling in T cells promotes expression of RORγt. Expression of ß-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of ß-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of ß-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/ß-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Colitis/metabolism , Colon/metabolism , Colonic Neoplasms/metabolism , Inflammation Mediators/metabolism , Lymphocytes, Tumor-Infiltrating/metabolism , beta Catenin/metabolism , Animals , Binding Sites , CD4-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/metabolism , Chromatin Assembly and Disassembly , Colitis/genetics , Colitis/immunology , Colitis/pathology , Colon/immunology , Colon/pathology , Colonic Neoplasms/genetics , Colonic Neoplasms/immunology , Colonic Neoplasms/pathology , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Genes, APC , Hepatocyte Nuclear Factor 1-alpha , Humans , Lymphocyte Activation , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , T Cell Transcription Factor 1/genetics , T Cell Transcription Factor 1/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Wnt Signaling Pathway , beta Catenin/genetics
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