Abstract
Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3(Δ/Δ)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Δ/Δ) mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3(Δ/Δ) tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis.
Highlights
The importance of inflammatory mediators and cells in the tumor microenvironment has recently become the focus of much attention
Urethane-induced lung tumorigenesis was inhibited in Stat3D/D mice
We investigated the role of Stat3 in carcinogen-induced lung tumorigenesis
Summary
The importance of inflammatory mediators and cells in the tumor microenvironment has recently become the focus of much attention. Innate immune cells, such as macrophages, NK cells and dendritic cells, can destroy tumor cells when appropriately activated. Tumor-associated macrophages have been shown to promote cancers, partly through their ability to secrete angiogenic, metastatic, and growth factors [1]. Another related myeloid lineage, myeloid-derived suppressor cells, which are increased in cancers, suppress antitumor immunity and directly contribute to tumor growth [7]. Myeloid-derived suppressor cells, which are increased in cancers, suppress antitumor immunity and directly contribute to tumor growth [7] It remains controversial how inflammation and immunity influence tumorigenesis
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