Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN

Cancer Cell. 2009 Sep 8;16(3):183-94. doi: 10.1016/j.ccr.2009.06.017.

Abstract

TGF-beta blockade significantly slows tumor growth through many mechanisms, including activation of CD8(+) T cells and macrophages. Here, we show that TGF-beta blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b(+)/Ly6G(+) tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-beta blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8(+) T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8(+) T cells intratumorally. Together, these data suggest that TGF-beta within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-beta blockade results in the recruitment and activation of TANs with an antitumor phenotype.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Azabicyclo Compounds / pharmacology
  • CD11b Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Polarity / genetics
  • Cell Polarity / immunology*
  • Cell Transformation, Viral
  • Cytokines / genetics
  • Cytokines / immunology
  • Immunohistochemistry
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Mesothelioma / genetics
  • Mesothelioma / immunology
  • Mesothelioma / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neutrophils / immunology*
  • Neutrophils / pathology
  • Phenotype
  • RNA, Messenger / metabolism
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antigens, Ly
  • Azabicyclo Compounds
  • CD11b Antigen
  • Cytokines
  • Ly6G antigen, mouse
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • SM16 compound
  • Transforming Growth Factor beta