Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis

Lingyan Wu, Hong Du, Yuan Li, Peng Qu, Cong Yan

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Abstract

Signal transducer and activator of transcription 3 (Stat3) is a potent transcription factor with diverse biological functions. Overexpression of constitutively active form Stat3C in lung alveolar type II (AT II) epithelial cells in CCSP-rtTA/(tetO) 7-CMV-Stat3C bitransgenic mice induces chronic inflammation and lung bronchioalveolar adenocarcinoma. In the present study, the population of CD11b +Gr-1 + myeloid-derived suppressor cells (MDSCs) was significantly increased in lung and blood of doxycycline-treated bitransgenic mice, but CD4 + and CD8 + T cells were decreased. In bronchioalveolar lavage fluid and plasma of doxycycline-treated bitransgenic mice, concentrations of MDSC-stimulating cytokines IL-1β, IL-6, IL-10, IL-13, INF-γ, TNF-α, and GM-CSF were significantly increased, which stimulated alveolar monocytes/macrophages to CD11b +Gr-1 + cell conversion in vitro. Phosphorylation of proto-oncogenic intracellular signaling molecules Stat3, Erk1/2, and P38 was significantly increased in CD11b +Gr-1 + cells from lung and blood of doxycycline-treated bitransgenic mice. CD11b +Gr-1 + cells from lung of doxycycline-treated bitransgenic mice strongly inhibited proliferation and function of wild-type CD4 + T cells in vitro. These findings support the concept that persistent activation of Stat3 induces inflammation during lung cancer by promoting MDSC-mediated immune suppression.

Original languageEnglish
Pages (from-to)2131-2141
Number of pages11
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
StatePublished - Oct 2011

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STAT3 Transcription Factor
Doxycycline
Carcinogenesis
Lung
Inflammation
T-Lymphocytes
Alveolar Epithelial Cells
Interleukin-13
Alveolar Macrophages
Bronchoalveolar Lavage
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-1
Interleukin-10
Monocytes
Interleukin-6
Lung Neoplasms
Blood Cells
Transcription Factors
Phosphorylation
Myeloid-Derived Suppressor Cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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title = "Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis",
abstract = "Signal transducer and activator of transcription 3 (Stat3) is a potent transcription factor with diverse biological functions. Overexpression of constitutively active form Stat3C in lung alveolar type II (AT II) epithelial cells in CCSP-rtTA/(tetO) 7-CMV-Stat3C bitransgenic mice induces chronic inflammation and lung bronchioalveolar adenocarcinoma. In the present study, the population of CD11b +Gr-1 + myeloid-derived suppressor cells (MDSCs) was significantly increased in lung and blood of doxycycline-treated bitransgenic mice, but CD4 + and CD8 + T cells were decreased. In bronchioalveolar lavage fluid and plasma of doxycycline-treated bitransgenic mice, concentrations of MDSC-stimulating cytokines IL-1β, IL-6, IL-10, IL-13, INF-γ, TNF-α, and GM-CSF were significantly increased, which stimulated alveolar monocytes/macrophages to CD11b +Gr-1 + cell conversion in vitro. Phosphorylation of proto-oncogenic intracellular signaling molecules Stat3, Erk1/2, and P38 was significantly increased in CD11b +Gr-1 + cells from lung and blood of doxycycline-treated bitransgenic mice. CD11b +Gr-1 + cells from lung of doxycycline-treated bitransgenic mice strongly inhibited proliferation and function of wild-type CD4 + T cells in vitro. These findings support the concept that persistent activation of Stat3 induces inflammation during lung cancer by promoting MDSC-mediated immune suppression.",
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T1 - Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis

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