Abstract 2830: The impact of gut microbial toxins and PGE2 on IL-23 production and its role in obesity associated colorectal tumorigenesis
Authors: Panneerselvam Janani , Madka Venkateshwar , Rai Rajani , Chandrakesan Parthasarathy , Houchen Courtney W. , Sanghera Dharambir K. , Morris Katherine T. , Rao Chinthalapally V. 
Published: September 2020

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Studies indicate that excessive intake of high-fat diet (HFD) promotes CRC by modulating gut microbiome-associated inflammatory mediators. Recent evidence suggests that interleukin-23 (IL-23) plays an important role in the impact of a HFD on obesity, the gut microbiome and colon carcinogenesis. Our study aimed to elucidate the role of IL-23 in obesity associated CRC and explore an anti-IL-23 approach for prevention and treatment. First we profiled human plasma (n=15/arm) for circulating IL-23 levels and found significantly higher levels (p&lt;0.0001) in obese individuals (BMI&gt;30). In addition, IL-23 expression was evaluated in colonic tumors from both humans and preclinical rodent models. Data from the Cancer Genome Atlas showed significant over expression (p&lt;0.0001) of IL-23A in CRC tumors (n=262) compared to normal tissue (n=41). This overexpression correlated with reduced disease free survival. Levels of both IL-23 and its receptor (IL23R) were evaluated in matched human CRC tissues by western blot and IHC and confirmed overexpression in CRC. IL-23 was also upregulated in colonic tumors from both sporadic (AOM-induced rat CRC) and FAP (Apcmin/+ mouse) rodent models when compared to matched normal mucosa. These data reveal a clear association of IL-23 overexpression with both obesity and colonic tumorigenesis.

To understand IL-23 production in the context of gut microbial toxins and prostaglandin (PG)E2 levels, we performed several mechanistic studies to mimic the tumor microenvironment. To elucidate PGE2-mediated regulation of IL-23 in colon tumorigenesis we studied both macrophages and dendritic cell lines in in vitro and ex vivo conditions. The immune cells treated with either PGE2 or bacterial toxins (LPA/LTA) showed a significant increase in IL-23 expression which associated with macrophage polarization and dendritic cell phenotypic changes. Interestingly, when CaCo2 cancer cells were co-cultured with PGE2/LTA-LPA-educated macrophages or dendritic cells, the cancer cells displayed enhanced IL-23 expression along with increased tumor cell proliferation and self-renewal. Upon addition of human recombinant IL-23 directly to cancer cells (CaCo2 and HCT116), the cells exhibited increased IL-23R expression along with enhanced self-renewal, cell migration and invasive properties as well as loss of epithelial barrier permeability. In ex-vivo experiments we found that treatment of rat colon tumors with PGE2 increased the expression of IL-23 compared to normal mucosa. Overall our study results demonstrate that IL-23 is associated with both obesity and poor survival of CRC patients and that PGE2 and gut microbe toxins play an important role in IL-23-associated colonic tumor progression. This newly identified nexus represents a potentially important target for prevention of obesity associated colorectal cancer.

Citation Format: Janani Panneerselvam, Venkateshwar Madka, Rajani Rai, Parthasarathy Chandrakesan, Courtney W. Houchen, Dharambir K. Sanghera, Katherine T. Morris, Chinthalapally V. Rao. The impact of gut microbial toxins and PGE2 on IL-23 production and its role in obesity associated colorectal tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2830.