Tuesday, April 23, 2024
4/23/2024
Robert A. Saxton | K22 (PAR-18-467) | Project Summary / Abstract Although inflammation is essential for protecting organisms against infection, excessive or chronic inflammation is also associated with an increased risk of certain cancers. This is particularly true at epithelial barriers such as the colonic mucosa in the gastrointestinal (GI) tract, which are in frequent contact with the external environment and therefore particularly susceptible to damaging inflammatory responses. Indeed, over 20% of patients with inflammatory bowel disease (IBD) will go on to develop colitis-associated cancer (CAC). Moreover, most therapeutic options for autoinflammatory diseases like IBD involve the use of immunosuppressive drugs, which may also increase tumor incidence due to reduced immunosurveillance. An alternative approach is to exploit natural mechanisms of tissue protection and repair in order to reduce tumor-promoting inflammation without suppressing anti-tumor immune responses. Recently, several members of the IL-20 cytokine family have been shown to be upregulated in both IBD and GI cancers, but their functional roles in these contexts are not fully understood. This includes the cytokines IL-19, IL-20, and IL-24, all of which signal through the shared receptor subunit IL-20Rß. However, whether this upregulation drives disease pathology or reflects a beneficial but insufficient homeostatic response remains unclear. This is largely due to the combinatorial and interconnected nature of receptor sharing within this family, resulting in a high degree of functional pleiotropy and redundancy that hinders experimental interrogation of these pathways. In this project, we will employ structure-guided protein engineering to deconvolute the pleiotropic functions of IL-20Rß ligands in inflammation-associated colon cancer. We will first use a combination of directed evolution and structure-based rational protein design to develop a pharmacological toolkit, comprising IL-20 receptor agonists and antagonists with altered receptor specificities, allowing us to selectively modulate the activity of individual IL-20Rß ligands. We will then use these tools in vivo to probe the effect of these engineered proteins in the development, progression, and gene expression changes over the course of colitis induction and tumor progression, using the well-established AOM/DSS mouse model of CAC. Together, these studies will provide important insights into the protective and pathogenic functions of distinct IL-20Rß ligands in CAC, while also directly testing the therapeutic potential of our engineered cytokine variants in the prevention of inflammation associated cancer.
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