The incidence of colorectal cancer (CRC) is increasing and the prognosis for patients with advanced or metastatic disease is relatively poor. Immunotherapies hold great promise, but deploying them effectively in CRC patients will require further knowledge of the complex cellular and molecular interactions that occur between intestinal tumours and the host immune system. The objective of this study is to understand the mechanisms by which lack of immune cell regulation in the gut can drive the formation of colon adenocarcinomas. In addition, this work aims to identify new mechanisms involved in progression to metastatic disease. Using mouse model systems, we found that aberrant activity of Treg cells deficient in IL-10 can promote inflammation-driven CRC. IL-10 deficient Tregs have increased capacity to drive tumourigenesis compared to their CD4<sup>+</sup> effector T cell counterparts. RNA sequencing revealed specific upregulation of several genes, including a newly-described cytokine, in tumour-promoting Tregs. We explored cytokine regulation and the tumour microenvironment, and show that the inflammatory cytokine IL-6 and TGFÎ2 are necessary for tumour formation in this model. Moreover, disease is associated with a marked stromal cell signature that is induced as a consequence of Treg deficiency in IL-10 production. Gp38<sup>+</sup> stromal cells are dominant producers of IL-6, and potent ECM modellers. Furthermore, tumours driven by IL-10 deficient Tregs express high amounts of the pro-mesenchymal transcription factor Sox4. Using combined in vitro and in vivo analyses, we confirm that Sox4 is involved in tumour growth and characterise its expression in CRC patients. Collectively, our findings suggest that Tregs and stromal cells act together to foster a microenvironment that promotes disease progression, notably through the expression of Sox4 in tumour cells. These findings open an exciting avenue to explore the phenotype of tumour-promoting Tregs and to study Sox4 function in metastatic disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:748710 |
| Date | January 2017 |
| Creators | Franchini, Fanny |
| Contributors | Powrie, Fiona M. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:2314081e-8c3f-43c7-9ea6-edf43430a43c |
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