Abstract 3181: IL-23 knockdown profoundly suppresses intestinal tumorigenesis in APCmin mice
Authors: Madka Venkateshwar , Chiliveru Srikanth , Pathuri Gopal , Panneerselvam Janani , Rai Rajani , Stratton Nicole C. , Kumar Nandini B. , Zhang Yuting , Rao Chinthalapally V 
Published: June 2022

Colorectal cancer (CRC) is the 3rd most common cancer in the US with an estimated 149,500 new cases and 52,980 deaths in 2021. Studies show that Western-style diet-induced obesity promote CRC by modulating gut inflammatory mediators. We found significant increase in IL-23 levels (p&lt;0.0001) in obese human subjects' plasma (n=15/arm; BMI&gt;30) and its. over expression in colonic tumors (CT) from human and rodent models that highly correlated with, the TCGA gene expression & disease-free survival data. These findings suggested IL-23 as a possible important link between obesity and colon tumorigenesis. The present study was designed to understand the role of IL-23 in colorectal carcinogenesis by using genetic knockout (KO) approach. For this study, Apcmin/+ and IL-23 KO mice were crossbred to generate Apcmin/+ mice with IL-23 in heterozygous or KO conditions. To determine the effect of IL-23 on intestinal tumorigenesis, six-week-old Apcmin/+ mice (N≥15/gender) were grouped by IL-23 genotype i.e., normal (+/+), heterozygous (+/-) and KO (-/-) conditions, then maintained under standard conditions. At 20 weeks of age, all mice were euthanized and intestines were evaluated and compared for tumors incidence and multiplicity. Genetic ablation of IL-23 led to significant suppression of large and small intestinal tumors of APCmin/+ mice in both genders. CT multiplicity of male and female IL-23+/+ Apcmin/+ mice were 1.35±0.16 (Mean±SEM) and 0.61±0.13, respectively. Male and female IL-23+/- Apcmin/+ mice had 77% (0.31+0.15; p&lt;0.0001) and 90% (0.06+0.09; p&lt;0.002) inhibition of CTs, respectively. Interestingly, IL-23 KO led to further suppression in male mice (96% inhibition in male; 0.05+0.05; p&lt;0.0001 and 90% in females; 0.06+0.06; p&lt;0.0001). While IL-23+/+ Apcmin/+ mice was 91% and 52% CT incidence in the male and female mice, respectively. CT incidence was suppressed by 72% (male, p&lt;0.0001) & 88% (female, p&lt;0.005) in the IL-23+/- mice, with further suppression to 95% (male, p&lt;0.0001) & 89% (female, p&lt;0.0025) inhibition in IL-23 KO mice. The strong suppressive effect of IL-23 knockdown was also observed on the small intestinal polyps (SIP) multiplicity. There was a 54% (12.56±1.64; p&lt;0.0001) and 58% (11.45±1.03; p&lt;0.0001) reduction in SIP number in IL23+/- and IL23-/- male Apcmin/+ mice, compared to the IL-23+/+ control mice (27.48±2.38). In female, 55-59% (13.88±1.05 and 12.73±2.03; p&lt;0.0001) less SIP were observed with IL-23 ablation compared to control (30.90±2.54). Apcmin/+ with IL-23 KO showed significant reduction in circulating proinflammatory cytokine and chemokines (Ex: IL-1, IL-10, IL-17, IL-23, CCL-2, CCL-3, CCL-5, TNFa, IFNg) levels compared to IL-23 WT mice. These results clearly demonstrate the colon tumor-promoting role of IL-23 and strengthens our hypothesis to explore this target for CRC prevention in high-risk obese individuals. (Supported in part by P30 CA225520 and Kerley-Cade Endowed Chair)

Citation Format: Venkateshwar Madka, Srikanth Chiliveru, Gopal Pathuri, Janani Panneerselvam, Rajani Rai, Nicole C. Stratton, Nandini B. Kumar, Yuting Zhang, Chinthalapally V Rao. IL-23 knockdown profoundly suppresses intestinal tumorigenesis in APCmin mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3181.