Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

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 to Rb1+/- mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induces 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, while higher IL23 expression is associated with worse survival in man. 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 pro-inflammatory IL23/IL12 axis.