Periodic Reporting for period 2 - WORMTUMORS (Worm power: Can helminths modify the development of colorectal cancer?)
Reporting period: 2017-08-01 to 2018-07-31
We have found that helminth infection increases inflammation and tumor development in a mouse model of disease. Changes in diet to one rich in fatty acids consumed in HIC also increased disease. Diet change clashed with underlying helminth infection resulting in a very poor outcome in this model. Increases in colorectal cancer following helminth infection and diet change are reliant on live helminth infection and are regulated by IL-4Ra signalling. Increased tumour development is associated with a reduced anti-tumor response and the increased production of inflammatory lipid mediators in the colon, where administration of one mediator increased tumor formation in naive mice. We conclude that helminth infection and diet change exacerbate colorectal cancer through regulation of fatty acid metabolism and increased production of lipid inflammatory mediators.
Thorough analysis of the immune system demonstrated that helminth infection could modify both innate and adaptive anti-tumor responses; and in particular, reduce IFN-gamma production by CD4+ and CD8+ T cells (typical anti-tumor responses) (Fig. 4). Although helminth infection was associated with typical type-2 responses, use of infected mice deficient in the signaling molecule required for generation of this response (IL-4Rα) actually exhibited worse disease (increased weight loss, mortality and tumor formation) than naive mice (Fig. 5). These results reveal an unexpected role for IL-4Rα signaling in protecting against helminth induced CRC. Through extensive lipidomics we found that increased CRC was associated with the production of certain lipid inflammatory mediators in the colon (Fig. 6). One of these mediators increased tumor formation in naive mice (Fig. 7). We conclude that helminth infection and diet change exacerbate inflammation-associated colorectal cancer through regulation of fatty acid metabolism and the production of inflammatory lipid mediators. These results were presented at the Cardiff Infection and Immunity Meeting (Nov 2017), the Molecular and Cellular Biology of Helminth Parasites meeting in Hydra (Sept 2018) and have been assembled for publication (anticipated Jan 2019).
We have also shown that administration of H. polygyrus excretory/secretory products (HES) but not H. polygyrus adult antigen increases tumour growth in vivo. This increase in tumor burden was associated with a significant increase in the total number of CD3+CD4+Foxp3+ regulatory T cells (Treg) within the draining lymph node of the tumor, as well as the tumor itself (Fig. 8). We have begun to explore how parasite products can drive tumor growth in vivo. These results were presented at the SASBMB meeting (July 2018), the Molecular and Cellular Biology of Helminth Parasites meeting in Hydra (Sept 2018) and are being assembled for publication (anticipated 2019).
As part of NRF funding I have received, I am supervising a PhD student working on research related to this project. The MSc student also funded by NRF on a project allied to this research recently submitted her MSc thesis and has secured a PhD studentship, with full scholarship, at Oxford University, UK. We recently published some of the work from her MSc in Scientific Reports (July 2018). Both studentships have allowed for the strengthening of the international collaboration I have established, between Cardiff University and UCT and set a platform for the development of this research at the host institution (a developing country). This has wider implications for strengthening scientific strengths in South Africa, building on the research taking place in this country and with international collaborators.