Novel Roles of SOCS3 as a Tumour Suppressor

Jewers, Chloe and Rigby, Rachael (2024) Novel Roles of SOCS3 as a Tumour Suppressor. Masters thesis, Lancaster University.

Text (2024JewersMRes)
2024JewersMRes.pdf - Published Version
Download (2MB)

Abstract

Cancer is a collection of diseases that were responsible for approximately ten million deaths in 2020. Colorectal cancer (CRC) is the third most common type of cancer; it occurs following the transformation of normal epithelial cells to adenocarcinoma which can eventually result in metastasis. Treatments are continuously being researched and developed, with immunotherapy becoming an increasingly common area of research against cancer. The enzyme indoleamine 2,3-dioxygenase (IDO) has been identified as a cause of tumour immune tolerance through the creation of a tryptophan-starved state in cells. Hence, blockers to IDO have been studied to test their efficacy in treating cancers. IDO blocker Epacadostat has been found to be effective in mice but has proven to be variable in success in human trials. Another IDO blocker under investigation is 1-methyl-D-tryptophan (1-MT). This project aimed to investigate the impact of the loss of tumour suppressor, SOCS3, on 1-MT treatment due to its ability to regulate IDO expression. SOCS3 silencing has been associated with some human cancers, therefore this study used conditional intestinal epithelial SOCS3 knockout mice (IECS3-/-) to recapitulate the loss of SOCS3 in intestinal adenocarcinoma. An azoxymethane/ dextran sodium sulphate (AOM/DSS) model was used to induce colon cancer and conditional knockout, or wild-type mice were administered either 1-MT or water. Analysis of the intestinal macrophages was performed using immunohistochemistry, IDO activity assessed using HPLC, and cell culture techniques to investigate impact of 1-MT in vitro. A decrease in M1 pro-inflammatory macrophages was found in the colon of IECS3 -/- 1-MT treated mice, and an increase in CD206+ IBA1- cells (potential immature dendritic cells (IDCs)) in IECS3-/- H2O treated mice. These findings indicate that a SOCS3 deficiency may play a role in reducing the efficacy of 1-MT immunotherapy treatment, presenting itself as a potential biomarker that could help identify patients who are likely to see improved prognosis following IDO-inhibitor treatment.