P099 IL-33 activates CD73-expressing cells promoting tumorigenesis during colitis-associated colorectal cancer

Abstract Background Colorectal cancer associated to chronic colitis (CAC) has a different pathogenesis compared sporadic or familial colorectal and represents the major complication of IBD. IL-33 its receptor, ST2, are important factors in Emerging evidence suggests potential contribution inflammation-driven tumorigenesis that can lead CAC. The aim our study was characterize precise IL-33/ST2 axis azoxymethane (AOM)/dextran sodium sulfate (DSS) model Methods C57/BL6 wild-type (WT), Il33-/-, T1/St2-/- Nt5e-/- mice were given single dose AOM followed by two cycles 3% DSS for 7d drinking water. Vehicle-treated WT served as controls sacrificed at same time points. Another group protocol received CD73 inhibitor i.p. treatment vehicle. Disease Activity Index, endoscopic, stereomicroscopic histological evaluations colons performed. IHC, immunofluorescence (IF), qPCR, ELISA done on full-thickness colons. RNA-Seq performed whole tissues from AOM/DSS treated WT, Il33-/- T1/St2-/-. qPCR analysis isolated polyps Nt5e (CD73) adenosine pathway targets. Results Il33, Ilrl1(ST2L), Ilrl1(sST2) mRNA transcripts, well total ST2 proteins dramatically elevated AOM/DSS-treated vs. controls. IHC IF revealed localization colonic epithelium cells within polyp LP morphologically consistent with stromal mast cells. Using IF, co-localized sub-epithelial myofibroblast markers Actin Vimentin, cell Tryptase MCPT1. resulted significant decreased number size colonoscopy revealing development protruding lesions abnormal vascular patterns, suggesting tumorous mice, while all deficient showed their absence more impressive mucosal inflammation, likely due reduced epithelial proliferation repair caused deficiency signaling. identified reduction targets T1/St2-/-vs. WT. confirmed this observation. Therapeutic inhibition produced similar results. Conclusion Our results suggest promotes CAC through activation CD73. Further studies underway determine mechanisms action support these findings.