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Article Dans Une Revue Cancer Discovery Année : 2019

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

Maya Kansara
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Kristian Thomson
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Puiyi Pang
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Lisa Mirabello
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Jean-Philippe Pin
Elizabeth Demicco
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Juming Yan
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Michele W.L. Teng
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Michele W L Teng
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Mark J Smyth
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David M Thomas
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Résumé

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.
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Dates et versions

hal-02398127 , version 1 (17-12-2020)

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Maya Kansara, Kristian Thomson, Puiyi Pang, Aurélie Dutour, Lisa Mirabello, et al.. Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23. Cancer Discovery, 2019, 9 (11), pp.1511-1519. ⟨10.1158/2159-8290.CD-19-0154⟩. ⟨hal-02398127⟩
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