Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting

Cancer Cell. 2012 Oct 16;22(4):479-93. doi: 10.1016/j.ccr.2012.08.016.

Abstract

Inflammation can promote or inhibit cancer progression. In this study we have addressed the role of the proinflammatory cytokine thymic stromal lymphopoietin (TSLP) during skin carcinogenesis. Using conditional loss- and gain-of-function mouse models for Notch and Wnt signaling, respectively, we demonstrate that TSLP-mediated inflammation protects against cutaneous carcinogenesis by acting directly on CD4 and CD8 T cells. Genetic ablation of TSLP receptor (TSLPR) perturbs T-cell-mediated protection and results in the accumulation of CD11b(+)Gr1(+) myeloid cells. These promote tumor growth by secreting Wnt ligands and augmenting β-catenin signaling in the neighboring epithelium. Epithelial specific ablation of β-catenin prevents both carcinogenesis and the accumulation of CD11b(+)Gr1(+) myeloid cells, suggesting tumor cells initiate a feed-forward loop that induces protumorigenic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11b Antigen / analysis
  • CD4-Positive T-Lymphocytes / physiology
  • Cytokines / physiology*
  • Hematopoietic System / cytology
  • Immunoglobulins / physiology
  • Inflammation / complications
  • Inflammation / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / physiology
  • Receptors, Cytokine / physiology
  • Receptors, Notch / physiology
  • Skin / immunology*
  • Skin Neoplasms / etiology*
  • Skin Neoplasms / prevention & control
  • Wnt Signaling Pathway
  • beta Catenin / physiology

Substances

  • CD11b Antigen
  • Cytokines
  • Immunoglobulins
  • Receptors, Cytokine
  • Receptors, Notch
  • Tslpr protein, mouse
  • beta Catenin
  • thymic stromal lymphopoietin