Abstract A011: Effect of IL-23 knockdown on obesity driven CRC in high-fat diet fed Apcmin/+ mice

Abstract Colorectal cancer (CRC) is the 3rd common cancer in the United States with an estimated 151,030 new cases and 52,580 deaths in 2022. Several studies suggest that western-style diet-induced obesity contributes to CRC promotion via systemic inflammatory mediators. Recently, we have reported significant elevation of circulating IL-23 levels in obese human subjects (BMI>30). Also, TCGA gene expression data indicated IL-23A over expression in colonic tumors (CT) that correlated with tumor stage, patient obesity, nodal metastasis, and poor survival rates. Importantly, we have shown that IL-23 knockdown in Apc min/+ mice led to significant suppression of the intestinal tumors strongly supporting our hypothesis that pro-inflammatory cytokine IL-23 could be a possible link between obesity and CRC. Here we explored the contribution of IL-23 in obesity induce CRC in vivo using high-fat diet (HFD) fed Apc min/+ mouse model. For this study, Apc min/+ and IL-23 KO (IL-23A p19-/- mice; MMMRC) were cross-bred to generate Apc min/+ mice with IL-23 normal (IL-23+/+) or KO (IL-23-/-) genotypes. Six-week old Apc min/+ mice (N≥15/gender) were grouped by IL-23 genotypes and fed HFD (60 Kcal) until termination. Mice were euthanized at 20 weeks age, intestines were harvested and evaluated for tumors incidence and multiplicity. In Apc min/+ mice, IL-23 deletion had significant suppressive effect on HFD driven CT and small intestinal tumors (SIT). IL-23-/- Apc min/+ male mice had 50% less CT (0.81+0.25 vs 1.61±0.27; p<0.05) while female mice had 40% less CT (0.40±0.16 vs 0.94±0.21; p=0.05) compared to the IL-23+/+ Apc min/+ control mice. Similarly, CT incidence was also suppressed by 36% and 48% in male and female IL-23-/- Apc min/+ mice respectively compared to control mice. SIT multiplicity was also inhibited by 48% in male (15.00±1.13 vs 28.54±1.11; p<0.0001) and by 41% in female (14.83±1.35 vs 25.18±1.71; p<0.0005) IL23-/- Apc min/+ compared to control mice. Tumor data was complemented by significant reduction in markers of proliferation, immune evasion, circulating proinflammatory cytokine and chemokines (IL-1, IL- 17, IL-23, IL-10, CCL-3, CCL-2, CCL-5, IFNγ, TNFα, etc.) in IL-23 KO compared to control mice. Our data clearly indicates that IL-23 is a promising target for CRC prevention in high-risk obese individuals and warrants further investigation. (Supported in part by P30CA225520 and Kerley-Cade Endowed Chair). Citation Format: Venkateshwar Madka, Srikanth Chiliveru, Yuting Zhang, Nicole Stratton, Anh Bao, Nandini Kumar, Chinthalapally V. Rao. Effect of IL-23 knockdown on obesity driven CRC in high-fat diet fed Apcmin/+ mice [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A011.