Abstract
RORC1 promotes protumorigenic innate immunity by stimulating “emergency” myelopoiesis.
Major finding: RORC1 promotes protumorigenic innate immunity by stimulating “emergency” myelopoiesis.
Mechanism: RORC1 controls key transcriptional regulators to induce expansion of MDSCs and M2-polarized TAMs.
Impact: Targeted inhibition of RORC1 may prevent tumor growth and metastasis.
The rapid change in hematopoietic output that occurs in response to acute immunologic stress is known as “emergency” hematopoiesis, a process that is co-opted by tumors to enhance the generation of tumor-promoting myeloid cells. The response of T-helper cells expressing IL17A, which is controlled by retinoic acid–related orphan receptor C (RORC1), has been implicated in G-CSF–mediated emergency myelopoiesis, prompting Strauss and colleagues to investigate the role of the IL17A/RORC1 axis in cancer-related myeloid differentiation. Analysis of the myeloid compartment of tumor-bearing mice revealed that emergency hematopoiesis occurs early in tumor development and that RORC1 expression in myeloid cells is indicative of advanced protumorigenic inflammation. Genetic deletion of Rorc1 in hematopoietic cells impaired tumor growth and metastasis in multiple tumor models and resulted in a reduction in the tumor-induced expansion of undifferentiated myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) compared with wild-type mice, supporting a role for RORC1 in promoting cancer-associated myelopoiesis. Further investigation revealed that RORC1 stimulated the differentiation of early hematopoietic progenitor cells in the bone marrow into myeloid lineage cells in response to colony-stimulating growth factors by inducing the expression of CCAAT/enhancer binding protein β (C/EBPβ), a positive regulator of granulopoiesis, and inhibiting the expression of SOCS3 and BCL3, negative regulators of granulopoiesis. RORC1 regulated MDSC expansion by promoting CSF-mediated protection of immature MDSCs against apoptosis and suppressing neutrophil maturation, resulting in the survival of immature MDSCs. Concurrently, RORC1 enhanced the maturation of TAMs by inducing the lineage commitment transcription factors PU.1 and interferon regulatory factor 8 and promoted the M2 polarization of macrophages. Taken together, these results elucidate the role of RORC1 in the regulation and coordination of tumor-promoting myeloid cell expansion and differentiation and suggest targeted inhibition of RORC1 as a potential therapeutic strategy.
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