Dennis, Kristen L.

Significance We show that distinct subsets of mast cells (MCs) expand with sequential oncogenic events in small bowel cancer. Mucosal mast cells (MMCs) previously detected early during Trichinella spiralis infection expand in adenomatous polyps in an IL-10–dependent manner. Connective tissue mast cells (CTMCs), earlier shown to expand during the resolution of inflammation following clearance of T. spiralis, are independent of IL-10 and associate with the transition of polyps to adenocarcinoma. IL-33 upregulates the CTMC lineage-specific protease murine mast cell protease 6 (mMCP6). Ablation of mMCP6 attenuates tumor growth. Thus, tissue sentinel cells respond to oncogenic events and cellular transformation in effect to help promote cancer. Delineating the types of MCs present at various stages of disease offers actionable cellular targets for therapeutic intervention in disease progression.

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 APCΔ468 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. Cancer Immunol Res; 3(7); 806–14. ©2015 AACR.

Abstract 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 APCΔ468 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. Cancer Res; 73(19); 5905–13. ©2013 AACR.