Abstract 450: Signal transducer and activator of the transcription 3 induces de novo lung tumorigenesis by promoting myeloid-derived suppressor cells and immune suppression

Multiple transgenic mouse models from our laboratories demonstrated that lung alveolar type II (AT II) epithelial cells serve as progenitor cells for lung adenocarcinoma when various oncogenic molecules were overexpressed in AT II epithelial cells. Signal transducers and activators of the transcription 3 (Stat3) is a potent transcription factor with diverse biological functions. Previously, we demonstrated that overexpression of constitutively active form Stat3C in AT II epithelial cells of CCSP-rtTA/(tetO) 7 -CMV-Stat3C bitransgenic mice induced chronic inflammation and lung bronchioalveolar adenocarcinoma (Li Y et al, Cancer Res 2007; 67:8494-503). Approximately 800 downstream genes changed expression in this process by the GeneChip microarray analysis. Among these genes, a group of pro-inflammatory cytokines and chemokines were highly up-regulated at the very early stage (1-month doxycycline treatment) in AT II epithelial cells, suggesting a critical role of inflammation in tumor initiation. In the current study, we found that CD11b + Gr-1 + myeloid-derived suppressor cells (MDSCs) were significantly increased, while CD4 + and CD8 + T cells were decreased in the lung and blood of doxycycline-treated bitransgenic mice. In the bronchioalveolar larvage fluid (BALF) and blood plasma of doxycycline-treated bitransgenic mice, concentrations of MDSCs-stimulating factors IL-1beta, IL-6, IL-10, TNF-alpha and GM-CSF were significantly increased. In the in vitro study, BALF from doxycycline-treated bitransgenic mice stimulated wild type alveolar monocyte/macrophage to CD11b + Gr-1 + cell conversion. When incubated with isolated wild type alveolar monocytes/macrophages in vitro, GM-CSF was able to stimulate heterogeneous CD11b + Gr-1 + cell conversion in three gated areas (R1, R2, R3) by flow cytometry. IL-1beta, IL-6, TNF-alpha were able to stimulate the CD11b + Gr-1 + cell conversion in R1 and R2 areas. IL-10 was able to stimulate the CD11b + Gr-1 + cell conversion only in the R1 area. VEGF lacked the ability to stimulate monocyte/macrophage to CD11b + Gr-1 + cell conversion. MDSCs from the lung and blood of doxycycline-treated bitransgenic mice showed increased phosphorylation of oncogenic intracellular signaling molecules Stat3, Erk1/2 and P38. MDSCs from doxycycline-treated bitransgenic mice strongly inhibited proliferation and function of wild type CD4 + T cells in vitro. CD4 + T cells from doxycycline-treated bitransgenic mice showed much weaker activities of proliferation and lymphokine release. In addition, T regulatory cells (Treg) were increased in doxycycline-treated bitransgenic mice. These findings support a concept that persistent activation of Stat3 induces inflammation and lung cancer by promoting MDSCs-mediated immune suppression to facilitate tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2011-450