RORC1 Regulates Tumor-Promoting "Emergency" Granulo-Monocytopoiesis
RORC1 Regulates Tumor-Promoting "Emergency" Granulo-Monocytopoiesis
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DOI：
10.1016/j.ccell.2015.07.006
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发表时间：
2015-08-10
期刊：
影响因子：
50.3
通讯作者：
Sica, Antonio
中科院分区：
文献类型：
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作者：
Strauss, Laura;Sangaletti, Sabina;Sica, Antonio
癌症驱动的粒细胞-单核细胞生成刺激肿瘤促进髓系群体的扩增，主要是髓系来源的抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）。我们根据人和小鼠肿瘤携带者中视黄酸相关孤儿受体（RORC 1/ROR γ）的表达鉴定了MDSC和TAM的亚群。RORC 1通过抑制粒细胞生成的阴性（Socs 3和BcI 3）和促进粒细胞生成的阳性（C/EBID β）调节剂以及骨髓祖细胞定型和分化为单核细胞/巨噬细胞谱系的关键转录介质（IRF 8和PU. 1）来协调骨髓生成。RORC 1通过保护MDSC免于凋亡、介导TAM分化和M2极化以及限制成熟中性粒细胞的肿瘤浸润来支持肿瘤促进先天免疫。因此，造血区室中RORC 1的消融防止了癌症驱动的骨髓生成，导致肿瘤生长和转移的抑制。
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/ROR gamma) in human and mouse tumor bearers. RORC1 orchestrates myelopoiesis by suppressing negative (Socs3 and BcI3) and promoting positive (C/EBID beta) 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.