Abstract 2968: FTY720 inhibits mutant Kras-induced lung cancer via disrupting Stat3-S1PR1 vicious cycle and downregulating tumor PD-L1 expression

Abstract

Abstract Aberrant activation of signal transducer and activator of transcription 3 (Stat3) occurs in many cancers and plays a critical role in tumor progression. The system that Stat3-induced Sphingosine-1-phosphate receptor 1 (S1PR1) expression and the S1P-S1PR1 pathway reciprocally regulate Stat3 activity was considered a major positive feedback loop for persistent Stat3 activation in cancer cells and the cells of tumor microenvironment. Tumor cells expressing the ligand for the receptor programmed death-1 (PD-1), PD-L1, have been shown to increase apoptosis of antigen-specific human T-cell to evade the immune system. In this study, we determined the influence of disrupting Stat3-S1PR1 vicious cycle on tumor formation and PD-L1 expression in lung cancer. We have established mutant Kras-induced lung cancer mice model and found that Stat3 phosphorylation was elevated in tumor tissues of lung cancer. Treatment of lung cancer cells with AG490 (JAK2 inhibitor) inhibited Stat3 activation and AG490 administration to the mice decreased the numbers of lung cancer nodules, indicating that blockage of Stat3 activation could inhibit mutant Kras-induced lung cancer in mice. Similar effects were also detected by using Stat3 inhibitor, S3I-201. We found that lung cancer cells expressed more pStat3 showed higher PD-L1 expression levels than that of lower pStat3 expressing cells. Inhibition of Stat3 activation by AG490 decreased PD-L1 expression in vitro and in vivo, indicating that PD-L1 expression could be regulated by Stat3. Moreover, FTY720 (S1P antagonist) could inhibit S1PR1 expression, down-regulate Stat3 activity, pJAK1 expression and inhibit IL-6 secretion in lung cancer cell lines and causes inhibition of the mutant Kras-induced lung cancer in mice. Furthermore, FTY720 administration dose-dependently suppressed tumor PD-L1 expression in mice lung cancer tissues. Taken together, our study indicated that FTY720 could suppress mutant Kras induced-lung cancer formation via inhibiting persistent Stat3 activation and down-regulating tumor PD-L1 expression. Citation Format: Hsuan-Heng Yeh, Tsung-I Hsu, Jan-Jong Hung, Wen-Pin Su, Wu-Chou Su. FTY720 inhibits mutant Kras-induced lung cancer via disrupting Stat3-S1PR1 vicious cycle and downregulating tumor PD-L1 expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2968. doi:10.1158/1538-7445.AM2014-2968