Abstract 3821: Expression of WSX1 receptor in Lewis Lung Carcinoma promotes tumor growth
Authors: Denada Dibra, Jeffry Cutrera, Xueqing Xia, Shulin Li
Journal: Cancer Research (2010)

Abstract Our analysis of the interleukin (IL) 27 receptor WSX1 in a variety of human epithelial cells showed that WSX1 is expressed in human tumor epithelial cells. A few cell lines like HT29 and UM-SCC17A showed a 6.9-8.4-fold lower expression of WSX1 when compared to a normal epithelial cell line, NCM460, while most of the cell lines such as Hela, HCT116, and UM-SCC11A showed much higher levels of expression (ranging from 13-78 times higher than NCM460). The role of wsx1 expression in tumors has not been reported by others. In the oral squamous cell carcinoma cell line AT84 and the cervical cancer cell line TC1, we illustrated that overexpression of WSX1 resulted in inhibition of tumor growth via an NKG2D-depent mechanism (Can Res, 2009); however, our most recent results show that WSX1 plays a dual role. Overexpression of WSX1 in Lewis lung carcinoma (LLC) cells enhanced tumor growth in vivo, but it reduced tumor cell proliferation and clonogenic ability of these cells in vitro, which is also observed in the TC1 and AT84 cell lines. The observed phenomenon in LLC tumors is not dependent on the NKG2D pathway, as WSX1 overexpression does not induce NKG2D ligand expression. Considering that WSX1 is a receptor for IL27, we asked whether IL27 is indeed the factor that promotes tumor growth. Since IL27 could signal in both tumor and immune cells to promote tumor growth, we used either truncated WSX1 lacking an intracellular domain (IL27 unable to signal into tumors) or TCCR−/− mice (IL27 unable to signal into immune cells) to understand how IL27 affects WSX1-mediated tumor growth. Our data indicates that overexpression of truncated WSX1 promotes tumor growth even further than full length WSX1, demonstrating that IL27 signaling in tumors does not promote tumor growth. Moreover, IL27 signaling in immune cells does not explain how WSX1 promotes tumor growth, as LLC-WSX1 grows faster than GFP control in wildtype and TCCR−/− mice. Finally, treatment of LLC-WSX1-tumor bearing mice with IL27 inhibits rather than promotes tumor growth which fully excludes the role of IL27. Although WSX1-mediated promotion of LLC tumor growth is independent of NKG2D or IL27 pathways, it inhibits adaptive immune responses: overexpression of WSX1 inhibits accumulation of CD4+, CD8+, and dendritic cells in the tumor microenvironment. WSX1 does not only affect immune cells via paracrine signaling in the local tumor microenvironment, but also in an endocrine manner in distal organs such as the spleen, suggesting the release of secretable factors. Moreover, in immune-deficient mice (SCID), WSX1-positive tumor cells grow at the same rate as GFP control, once more confirming the role of WSX1 in attenuating adaptive immune responses to promote LLC tumor growth as the underlying mechanism. In conclusion, the presence of WSX1 in tumors attenuates the adaptive immune response via a mechanism independent of IL27 and the NKG2D pathway. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3821.