Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

Cancer Discov. 2019 Nov;9(11):1511-1519. doi: 10.1158/2159-8290.CD-19-0154. Epub 2019 Sep 16.


The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4-/- gene-targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1+/- mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23 -/- mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis. SIGNIFICANCE: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non-cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.See related commentary by Jones, p. 1484.This article is highlighted in the In This Issue feature, p. 1469.

MeSH terms

  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / immunology*
  • Bone Neoplasms / mortality
  • Cell Line, Tumor
  • Disease Progression
  • Humans
  • Interleukin-12 / metabolism
  • Interleukin-23 Subunit p19 / genetics*
  • Interleukin-23 Subunit p19 / metabolism
  • Mice
  • Myeloid Cells / immunology*
  • Neoplasm Transplantation
  • Osteosarcoma / genetics
  • Osteosarcoma / immunology*
  • Osteosarcoma / mortality
  • Receptors, Metabotropic Glutamate / genetics*
  • Receptors, Metabotropic Glutamate / metabolism
  • Survival Analysis
  • Up-Regulation


  • IL23A protein, human
  • Interleukin-23 Subunit p19
  • Receptors, Metabotropic Glutamate
  • Interleukin-12
  • metabotropic glutamate receptor 4