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Infiltrating myeloid cells drive osteosarcoma progression via GRM4 regulation of IL23.

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 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.

Type Journal
ISBN 2159-8274
Authors Kansara, M.; Thomson, K.; Pang, P.; Dutour, A.; Mirabello, L.; Acher, F.; Pin, J. P.; Demicco, E. G.; Yan, J.; Teng, M. W. L.; Smyth, M. J.; Thomas, D. M.
Responsible Garvan Author Dr Maya Kansara
Publisher Name Cancer Discovery
Published Date 2019-11-18
Published Volume 9
Published Issue 11
Published Pages 1511-1519
Status Published in-print
DOI 10.1158/2159-8290.Cd-19-0154