Cancer Cell
Volume 28, Issue 2, 10 August 2015, Pages 253-269
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Article
RORC1 Regulates Tumor-Promoting “Emergency” Granulo-Monocytopoiesis

https://doi.org/10.1016/j.ccell.2015.07.006Get rights and content
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Highlights

  • RORC1 drives cancer-related myelopoiesis in response to colony-stimulating factors

  • RORC1+ myeloid cells are a hallmark of tumor-promoting emergency myelopoiesis

  • RORC1 ablation in the hematopoietic compartment prevents generation of MDSCs and TAMs

  • RORC1 ablation in the hematopoietic compartment prevents tumor development

Summary

Cancer-driven granulo-monocytopoiesis stimulates expansion of tumor promoting myeloid populations, mostly myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We identified subsets of MDSCs and TAMs based on the expression of retinoic-acid-related orphan receptor (RORC1/RORγ) in human and mouse tumor bearers. RORC1 orchestrates myelopoiesis by suppressing negative (Socs3 and Bcl3) and promoting positive (C/EBPβ) regulators of granulopoiesis, as well as the key transcriptional mediators of myeloid progenitor commitment and differentiation to the monocytic/macrophage lineage (IRF8 and PU.1). RORC1 supported tumor-promoting innate immunity by protecting MDSCs from apoptosis, mediating TAM differentiation and M2 polarization, and limiting tumor infiltration by mature neutrophils. Accordingly, ablation of RORC1 in the hematopoietic compartment prevented cancer-driven myelopoiesis, resulting in inhibition of tumor growth and metastasis.

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