The Role of Myeloid Derived Suppressor Cells in the Interleukin-10 Model of Colitis-Associated Cancer
Abstract
Chronic inflammation in the colon is a risk factor for developing colorectal cancers, one of the leading causes of cancer related deaths in Canada. A hallmark feature of inflammation is the recruitment of leukocytes. Of interest in this thesis are the heterogenous population of Gr1+/CD11b+ Myeloid Derived Suppressor Cells (MDSC). These cells are recruited to tumour sites, but have recently also been shown to be increased during inflammation. A key regulator of inflammation and leukocyte recruitment to the gut is the innate immune receptor TLR4. In this thesis we use the IL-10-/- mouse model to examine the role of MDSC in colitis-associated cancer.
Our preliminary data in an IL-10 TLR4 double knock out mouse revealed an increased cancer incidence in the absence of TLR4. We hypothesized that MDSC contributed to cancer development in the IL-10-/- and TLR4 signaling modulates cancer development through an effect on MDSC function or recruitment.
Our studies demonstrated enhanced numbers of Gr1+/CD11b+ cells in the colons of IL-10-/- mice. Characterization of these cells revealed an active immunosuppressive phenotype demonstrated by activity of NOS II and Arginase I enzymes and suppression of T-cell proliferation. Pharmacological targeting of MDSC decreased dysplasia development. Enriching the MDSC pool using adoptive transfer was associated with enhanced neoplasia development in the IL-10-/- mice. These data suggest that MDSC contribute to inflammation associated tumour development.
In the absence of TLR4, IL-10-/- mice recruited increased levels of MDSC to the colon. MDSC numbers correlated with the levels of cancer development in this model. TLR4 competence did not affect the immunosuppressive function of MDSC. We identified MCP-1 and SDF-1 as MDSC chemoattractants. Examination of colonic tissue demonstrated increased MDSC chemoattractant expression levels in the absence of TLR4 before tumour development in the IL-10 deficient model.
Our data identify a link between TLR4 signaling and MDSC recruitment to the gut during inflammation and demonstrate that MDSC recruitment drives cancer development.
Description
Keywords
Biology
Citation
Bawa, M. (2015). The Role of Myeloid Derived Suppressor Cells in the Interleukin-10 Model of Colitis-Associated Cancer (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28335