Abstract

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.

Authors	Kansara, Maya; Thomson, Kristian; Pang, Puiyi; Dutour, Aurelie; Mirabello, Lisa; Acher, Francine; Pin, Jean-Philippe; Demicco, Elizabeth G; Yan, Juming; Teng, Michele W L; Smyth, Mark J; Thomas, David M
Journal	CANCER DISCOVERY
Pages	1511-1519
Volume	9
Date	1/09/2019
Grant ID	APP1113482
Funding Body	National Health and Medical Research Council (NHMRC)
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1158/2159-8290.CD-19-0154