Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

The glutamate metabotropic receptor 4 ( ) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that gene-targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with mice. GRM4 is expressed in myeloid cells, selectivel...

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Published inCancer discovery Vol. 9; no. 11; pp. 1511 - 1519
Main 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
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research 01.11.2019
Subjects
Biochemistry
Biochemistry, Molecular Biology
Biophysics
Biotechnology
Life Sciences
Molecular biology
Neurobiology
Neurons and Cognition
Pharmaceutical sciences
Pharmacology
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Summary:The glutamate metabotropic receptor 4 ( ) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that gene-targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell expression in a GRM4-dependent fashion, while suppressing the related cytokine . 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, 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. . .
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ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-19-0154