Colorectal cancer (CRC), the third leading cause of cancer deaths in the United States, is a challenging disease involving complex interplay among immune cells, cytokine-mediated pathways and gut microbiota ? leading to inflammation, disruption of the epithelial tissue barrier, acute colitis and CRC development. Thus, mechanistic studies are urgently needed to clarify the interactions and consequences of these key variables, enabling the identification of novel targets for therapeutic intervention. In the course of studies funded by our previous award (R01 CA101795), we identified TAK1 (TGF-beta-activated kinase 1) as a negative regulator of NF-?B signaling in neutrophils and found that its specific deletion in the myeloid lineage (Tak1?M/?M) leads to increased proinflammatory cytokines (IL-1?, IL-6, and TNF-?) and greater sensitivity to LPS-induced septic shock. Unexpectedly, Tak1?M/?M mice were completely resistant to chemically induced acute colitis and CRC development. This phenotype was associated with a marked accumulation of Th17 and ILC3 cells in the intestinal lamina propria and alterations of the gut microbiota composition. Further studies showed significant suppression of chemokine expression in colon epithelial cells and of immune cell trafficking into colon tissues. These intriguing new findings led us to hypothesize that specific gut microbiota, Th17 and ILC3 cells and their cytokines (IL-17 and IL-22) play critical roles in regulating resistance to colitis and inflammation-related CRC through the suppression of chemokine expression by colon epithelial cells. Key predictions of this hypothesis will be tested in three specific research aims, all relying on the Tak1?M/?M model of suppressed colitis and CRC tumorigenesis.
Aim 1 seeks to identify specific strains of microbiota that contribute to the accumulation of Th17 and ILC3 cells and thus to resistance to experimental colitis and CRC.
Aim 2 will define the functions of Th17 and ILC3 cells (and of their cytokines) in promoting resistance to chemically induced colitis and CRC, while Aim 3 will test the hypothesis that Th17/ILC3-derived cytokines inhibit the expression of chemokines by colon epithelial cells, thus blocking subsequent immune cell infiltration of the epithelial layer and ultimately the induction of malignant changes in the colon. Upon successful completion of this work, we expect to have a much-improved understanding of the inflammatory processes that drive the development of ulcerative colitis and CRC, and thus of potential vulnerabilities in this network that could be targeted for the prevention or treatment of these disorders.

Public Health Relevance

Inflammation responses in the colon have emerged as important contributors to colorectal cancer, but the networks of gut microorganisms, immune cells, cytokines and chemokines that participate in these responses and give rise to malignant changes in the colon are only beginning to be understood. The proposed studies, based on a novel animal model that resists inflammation-related colitis and cancer, will help to clarify these complex interactions, providing impetus for the development of more effective therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Daschner, Phillip J
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Methodist Hospital Research Institute
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Yu, Xiao; Du, Yang; Cai, Chunmei et al. (2018) Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity. Nat Commun 9:4964
Du, Yang; Duan, Tianhao; Feng, Yanchun et al. (2018) LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I for autophagic degradation. EMBO J 37:351-366
Xia, Lu; Wu, Jian; Pattaradilokrat, Sittiporn et al. (2018) Detection of host pathways universally inhibited after Plasmodium yoelii infection for immune intervention. Sci Rep 8:15280
Zhu, Motao; Ding, Xilai; Zhao, Ruifang et al. (2018) Co-delivery of tumor antigen and dual toll-like receptor ligands into dendritic cell by silicon microparticle enables efficient immunotherapy against melanoma. J Control Release 272:72-82
Ning, Bo; Zhao, Wei; Qian, Chen et al. (2017) USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components. Nat Commun 8:349
Zhang, Jindong; Zhang, Chuanxia; Cui, Jun et al. (2017) TRIM45 functions as a tumor suppressor in the brain via its E3 ligase activity by stabilizing p53 through K63-linked ubiquitination. Cell Death Dis 8:e2831
Wang, Rong-Fu; Wang, Helen Y (2017) Immune targets and neoantigens for cancer immunotherapy and precision medicine. Cell Res 27:11-37
Sheng, Si Yuan; Gu, Yong; Lu, Chuan Gang et al. (2017) The distribution and function of human memory T cell subsets in lung cancer. Immunol Res 65:639-650
Cai, Baowei; Wu, Jian; Yu, Xiao et al. (2017) FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions. MBio 8:
Jin, Shouheng; Tian, Shuo; Chen, Yamei et al. (2016) USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. EMBO J 35:866-80

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