Inhibiting Stat3 Signaling in the Hematopoietic System Elicits Multicomponent Antitumor Immunity

Nat Med. 2005 Dec;11(12):1314-21. doi: 10.1038/nm1325. Epub 2005 Nov 20.

Abstract

The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Bone Marrow Cells / immunology*
  • Cell Line, Tumor
  • Cytotoxicity Tests, Immunologic
  • Dendritic Cells / immunology*
  • Flow Cytometry
  • Gene Silencing
  • Immunohistochemistry
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Knockout
  • Neoplasms / immunology*
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes / immunology*

Substances

  • STAT3 Transcription Factor
  • Stat3 protein, mouse