Abstract 532: Nod1 functions in T cells to suppress inflammation-associated colorectal cancer
Authors: Maochang Liu, Fuyuan Wang, Michael Shaw, Gabriel Nunez, Grace Yi Chen
Journal: Cancer Research (2012)

Abstract A major risk factor for the development of colorectal cancer is the presence of chronic inflammation within the colon. Innate immune receptors have emerged as key players in regulating intestinal homeostasis and the development of colorectal cancer in mouse models. There are two major classes of innate immune receptors, the Toll-like receptors and the Nod-like receptors (NLRs), which are important in pathogen recognition and eradication, but are also capable of sensing commensal bacteria within the gut. We have previously demonstrated that the ubiquitously expressed NLR family member, Nod1, acts as a tumor suppressor in the setting of chronic inflammation. The purpose of the current study is to better understand how Nod1 suppresses tumor development, which would be important in developing a chemoprevention strategy for inflammation-associated colon carcinogenesis using available Nod1 ligands. Using a mouse model of colitis-associated colon cancer in which mice are given a single intraperitoneal injection of the carcinogen, azoxymethane, followed by multiple rounds of water containing dextran sulfate sodium to induce chronic colitis, we generated bone marrow chimeras to determine whether Nod1 functions to suppress inflammation-related tumors in the intestinal epithelial versus hematopoietic compartment. We also performed adoptive transfer experiments to specifically determine the role of Nod1 in T cells in tumor suppression. Finally, Nod1 mice were crossed with T-cell deficient, TCRβ-/- mice, to further determine T-cell intrinsic properties of Nod1 in limiting tumor potential. Real-time PCR analysis and cultures of colon lamina propria cells from wildtype and Nod1-deficient mice were performed to determine recruitment of and production of cytokines by T cells within the colon. Our studies suggest that Nod1 functions in the hematopoietic cell compartment to protect against inflammation-induced tumorigenesis. More specifically, adoptive transfer of wildtype T cells was capable of rescuing Nod1-deficient mice from developing significant numbers of tumors, suggesting that Nod1 signaling in T cells is important for tumor suppression. Consistent with a T cell-specific function for Nod1 in tumor suppression, adoptive transfer of Nod1-deficient T cells in either TCRβ-deficient or TCRβ/Nod1 doubly-deficient mice resulted in significant numbers of tumors in contrast to adoptive transfer of wildtype T cells, which resulted in fewer tumors. Cytokine expression analysis of colon tissue as well as colon lamina propria cells demonstrated that Nod1-deficient mice exhibit an impairment in IFN-γ production during inflammation. These studies suggest a T-cell intrinsic role for Nod1 in protecting against inflammation-associated colon neoplasia, which may be related to a defect in immune surveillance. These observations set the stage for development of Nod1 agonists as colon cancer chemopreventive agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 532. doi:1538-7445.AM2012-532