Abstract 794: Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression and lung tumorigenesis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Smoking-induced lung cancer is the leading death in cancer patients worldwide. Persistent inflammation plays a major role in promoting lung cancer in humans and animals. Since MMP12 over-expression is highly associated with smoking-induced inflammatory cell infiltration in the lung, characterization of MMP12 over-production will facilitate understanding initiation and progression of lung cancer and COPD (the major phenotype is emphysema) that are related to smoking. Matrix metalloproteinase 12 (MMP12) is a macrophage secreting proteinase. In order to fully understand the function of MMP12 in myeloid lineage cells, a myeloid-specific c-fms-rtTA/(TetO)7-CMV-MMP12 bitransgenic mouse model was created to mimic the clinical setting. In this bitransgenic system, MMP12-Flag fusion protein was expressed in myeloid lineage cells after doxycycline treatment. Induction of MMP12 abnormally elevated frequencies and numbers of the common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs), and decreased the frequency and number of the megakaryocyte/ erythrocyte progenitors (MEPs) in the bone marrow. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) was systemically increased. Oncogenic intracellular signaling molecules were highly activated in circulating CD11b+/Gr-1+ cells in multiple organs of doxycycline-treated bitransgenic mice, an indication of cell autonomous defect. In the serum, pro-inflammatory cytokines that are known to stimulate MDSCs expansion were highly induced in doxycycline-treated bitransgenic mice. MMP12 directly stimulated lineage negative (Lin-) progenitor cells to differentiate into MDSCs. Both in vitro and in vivo studies showed immunosuppressive function on T cell proliferation and function by MDSCs from doxycycline-treated bitransgenic mice. Both percentage and absolute numbers of Treg cells were increased in doxycycline-treated bitransgenic mice. It is known that Treg cells inhibit CD4+ T cells in cancer. MMP12 showed a direct inhibitory effect on proliferation and function of T cells in the in vitro study. In the lung, the concentration of interleukin (IL)-6 was increased, which aberrantly activated oncogenic signal transducer and activator of transcription 3 (Stat3) in tumor progenitor AT II epithelial cells and alveolar macrophages. Stat3 downstream genes were increased in AT II epithelial cells. As a consequence, spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 over-expression. Bone marrow chimeras studies confirmed that the MMP12-induced myeloid cell autonomous was responsible to abnormal myelopoiesis, immune suppression and lung adenocarcinoma. These results support a concept that MMP12 induces lung tumor through transforming AT II epithelial cell to cancerous cells and inhibit immune surveillance. 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 794. doi:10.1158/1538-7445.AM2011-794