Signal Transducer and Activator of Transcription 3 (Stat3C) Promotes Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis

Abstract

We have previously reported that persistent activation of the Stat3 signaling pathway, by overexpressing constitutively active Stat3C, in lung alveolar type II (AT II) epithelial cells directly induces spontaneous bronchioalveolar adenocarcinoma in CCSP-rtTA/(tetO) 7 -Stat3C bitransgenic mice. 1 The process is initiated by synthesis and induction of proinflammatory cytokines and chemokines in AT II epithelial cells, triggering heightened levels of inflammatory cell infiltration. Subsequent studies showed that persistent activation of Stat3 in AT II epithelial cells is a common phenomenon in inflammation-induced lung tumor animal models, as demonstrated by matrix metalloproteinase 12 (MMP12) and apoptosis inhibitor 6 (Api6) overexpression bitransgenic mouse models. 2-4 These findings suggested that Stat3 plays a critical role in mediating inflammation-induced lung adenocarcinoma formation. In a clinical setting, the expression of Stat3 and the genes it induces are increased in human lung adenocarcinoma and in chronic obstructive pulmonary disease, a disease similar in pulmonary impairment to lung cancer. 5 Both diseases are common in human smokers. A knockin mouse model also shows the enhanced tumorigenic power of the Stat3C molecule in mammary tumors. 6

Accumulation of Myeloid-Derived Suppressor Cells in the Lungs during Pneumocystis Pneumonia

“…A total of 5 ϫ 10 5 CD4 ϩ T cells were isolated from spleens of normal mice by magnetic separation as described previously (31) and then labeled with 5 M carboxyfluorescein succinimidyl ester (CFSE) (Invitrogen, Carlsbad, CA) at room temperature for 5 min. Cells were washed with PBS and incubated in RPMI 1640 medium at 37°C for 30 min.…”

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…Many of these molecules signal through STAT3, which also upregulates S100A9, a myeloid-related protein that prevented DC maturation resulting in accumulation of MDSCs (21,103,166). IL-10, conversely, inhibited MDSC-expansion by blocking IL-6 signaling through STAT3 (83).…”

Myeloid-specific expression of Stat3C results in conversion of bone marrow mesenchymal stem cells into alveolar type II epithelial cells in the lung

“…Expression of Api6 was identified for the first time in cultured BMSCs. By contrast, embryonic stem cell markers, such as OCT-4, BMP4 and SOX2, and Nanog, were expressed at relatively low levels under the same cultured condition (Table 2), even though Nanog and Sox2 showed increased expression in BMSCs at later culturing passages (11)(12)(13)(14)(15)(16)(17)(18)(19). This suggests that BMSCs and embryonic stem cells have different characteristics of marker expression, implicating differential function properties in vivo.…”