Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response

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Abstract
Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.
Funding Information
  • Faculty of Medical Sciences, University of Kragujevac (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)
  • Faculty of Medical Sciences, University of Kragujevac (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)
  • Serbian Ministry of Science (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)
  • Serbian Ministry of Science (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)
  • Swiss National Science Foundation (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)
  • Phillip Morris and Center for Leadership Development (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)
  • Start Up for Science (MP01/12, MP01/14, ON175103, ON175069, IZ73Z0_152454/1)

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