RORC1 Regulates Tumor-Promoting "Emergency" Granulo-Monocytopoiesis

Cancer Cell. 2015 Aug 10;28(2):253-69. doi: 10.1016/j.ccell.2015.07.006.

Abstract

Cancer-driven granulo-monocytopoiesis stimulates expansion of tumor promoting myeloid populations, mostly myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We identified subsets of MDSCs and TAMs based on the expression of retinoic-acid-related orphan receptor (RORC1/RORγ) in human and mouse tumor bearers. RORC1 orchestrates myelopoiesis by suppressing negative (Socs3 and Bcl3) and promoting positive (C/EBPβ) regulators of granulopoiesis, as well as the key transcriptional mediators of myeloid progenitor commitment and differentiation to the monocytic/macrophage lineage (IRF8 and PU.1). RORC1 supported tumor-promoting innate immunity by protecting MDSCs from apoptosis, mediating TAM differentiation and M2 polarization, and limiting tumor infiltration by mature neutrophils. Accordingly, ablation of RORC1 in the hematopoietic compartment prevented cancer-driven myelopoiesis, resulting in inhibition of tumor growth and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Granulocytes / metabolism*
  • Granulocytes / pathology
  • Humans
  • Immunohistochemistry
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Monocytes / metabolism*
  • Monocytes / pathology
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Myelopoiesis / genetics*
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Neutrophils / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Burden / genetics

Substances

  • Cytokines
  • Nuclear Receptor Subfamily 1, Group F, Member 3