Abstract 1521: Role of the guanylate-binding-protein 1 (GBP-1) in immunoediting of colorectal carcinoma.

Abstract

Abstract The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by IFN-γ in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), we previously reported that the expression of GBP-1 in the cells of the desmoplastic stroma correlates with the presence of an IFN-γ-dominated Th1 microenvironment and with an increased cancer-related 5-year survival. Moreover, GBP-1 expression in the blood vessels of CRC tissue was associated with a reduced angiogenesis. However, the expression and the role of GBP-1 in the tumor cells of CRC remained unknown. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-γ were unable to express GBP-1 indicating a reduced inducibility in colorectal tumor cells. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-γ and in vivo in IBD. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration, invasion and anchorage-independent growth. Using RNA interference, we showed that GBP-1 mediates the anti-proliferative, anti-migratory, anti-invasive and anti-clonogenic effects of IFN-γ in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether these results suggested that GBP-1 acts directly as a tumor suppressor in CRC by mediating the effects of IFN-γ. In addition, the loss of GBP-1 expression in tumor cells indicated that tumor evasion from the IFN-γ-dominated Th1 immune response might have occured. This was confirmed by showing, first, that the absence of GBP-1 inducibility in CRC cell lines correlates with resistance to the anti-proliferative and pro-apoptotic effects of IFN-γ and, second, that the resistant cell lines exhibit defects in the IFN-γ signaling pathway. Citation Format: Nathalie Britzen-Laurent, Karoline Lipnik, Matthias Ocker, Elisabeth Naschberger, Vera Schellerer, Roland Croner, Michael Vieth, Maximilian Waldner, Pablo Steinberg, Christine Hohenadl, Michael Stürzl. Role of the guanylate-binding-protein 1 (GBP-1) in immunoediting of colorectal carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1521. doi:10.1158/1538-7445.AM2013-1521