P076 Dock2 acts as a tumour suppressor via immune cell regulation of IDO1 in Inflammatory Bowel Disease–associated colorectal cancer

• Published in: Journal of Crohn's and colitis Vol. 18; no. Supplement_1; p. i347
• Main Authors: Churchhouse MD, A, Billard, C V, Pohl, S Ö, Donnelly, K, Suzuki, T, Von Kriegsheim, A, Arends, M J, Coffelt, S B, Myant, K B
• Format: Journal Article
• Language: English
• Published: 24.01.2024
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjad212.0206

Abstract Background Inflammatory Bowel Disease-associated colorectal cancer (IBDCRC) is a known and serious complication of Inflammatory Bowel Disease (IBD) affecting the colon. However, relatively little is known about the pathogenesis of IBD-associated colorectal cancer in comparison with its sporadic cancer counterpart. Mutations in Dock2 occur in around 10% of IBD-associated colorectal cancers. Methods We used an APC-mediated mouse model of inflammation-associated tumourigenesis. VilApcfl/+Dock2tm1b/tm1b and VilApcfl/+ (control) mice were subjected to chronic dextran sodium sulphate (DSS) colitis and aged. After tamoxifen induction, mice were given two seven-day rounds of 0.5% DSS, interspersed with normal drinking water, and then aged to 47 days before culling for analysis. Additionally in vitro, Apc deficient, tumourigenic colonic organoids were generated by deleting Apc from wild type and Dock2tm1a/tm1a colonic organoids using CRISPR/Cas9. Results We found that loss of Dock2 increases tumourigenesis (both in terms of tumour number and tumour burden) via immune dysregulation in an APC-mediated model of inflammation-induced tumourigenesis in vivo. The increased tumourigenesis observed is associated with a CD3 and gamma delta (γδ) T-positive immune cell infiltrate, an interferon gamma signature, and a significant upregulation of Ido1 (which catalyses the conversion of amino acid tryptophan to kynurenine). In tumours from VilApcfl/+Dock2tm1b/tm1b mice, tryptophan is reduced whilst the metabolite xanthurenate is increased, demonstrating IDO activity. Separately in vitro, we showed that epithelial IDO1 is induced by administration of interferon gamma. We demonstrated a source of this interferon gamma as γδ T cells, which are increased in tumours of mice lacking Dock2. Critically, inhibition of IDO1 (with 1-L-MT) abrogated the increased tumourigenesis observed as a result of Dock2 loss in mice. Conclusion Overall, we have identified a role for γδ T cells in promoting tumour initiation via Ido1 expression, using a Dock2 model to accentuate this phenotype.Further work is now needed to both fully characterise this novel pathway in IBDCRC, and establish how immune dysregulation promotes tumourigenesis, but it opens exciting potential for a therapeutic strategy in preventing cancer as a result of Inflammatory Bowel Disease.