Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation

Nat Commun. 2015 Apr 29;6:6840. doi: 10.1038/ncomms7840.

Abstract

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibitor of Differentiation Protein 1 / physiology*
  • Interferon Regulatory Factors / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Mice, Inbred C57BL
  • Myeloid Cells / physiology*
  • Neoplasm Metastasis
  • Transforming Growth Factor beta / metabolism

Substances

  • Inhibitor of Differentiation Protein 1
  • Interferon Regulatory Factors
  • Transforming Growth Factor beta
  • interferon regulatory factor-8