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首页> 外文期刊>Cancer Cell >Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors
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Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

机译：癌症相关的成纤维细胞通过诱导PMN-MDSC渗透肿瘤来中和CSF1受体阻断的抗肿瘤作用

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Summary Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects. Graphical Abstract Display Omitted Highlights ? PMN-MDSC infiltration of tumors is controlled by carcinoma-associated fibroblasts ? CSF-1 silences expression of granulocytic chemokines by CAF mediated by HDAC2 ? Inhibition of CSF-1R induced tumor infiltration by PMN-MDSC ? Combination of CSF-1R with CXCR2 inhibitors demonstrated strong anti-tumor effect Kumar et?al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.
机译：发明内容肿瘤相关的巨噬细胞（TAM）有助于肿瘤进展的所有方面。使用CSF1R抑制剂对靶TAM进行治疗吸引力，但抗肿瘤效应具有非常有限。在这里，我们已经确定了限制CSF1R靶向治疗的影响的机制。我们证明癌相关的成纤维细胞（CAF）是募集肉芽细胞对肿瘤的趋化因子的主要来源。由肿瘤细胞产生的CSF1导致HDAC2介导的CAF中粒细胞特异性趋化因子表达的下调，这将这些细胞迁移到肿瘤中。用CSF1R抑制剂治疗扰乱了这种串扰，并引发了肉芽细胞募集到肿瘤的深刻增加。将CSF1R抑制剂与CXCR2拮抗剂堵塞肿瘤肿瘤浸润性，表现出强烈的抗肿瘤作用。图形抽象显示省略了亮点？ PMN-MDSC肿瘤浸润由癌相关的成纤维细胞控制？ CSF-1沉默粒细胞趋化因子的CAF由HDAC2介导的CAF？ PMN-MDSC抑制CSF-1R诱导的肿瘤浸润？ CSF-1R与CXCR2抑制剂的组合证明了kumar等抗肿瘤作用。表明CSF1R抑制改变了癌症相关成纤维细胞的趋化因子分泌，其吸引了促肿瘤PMN-MDSC并导致效果不良。 CSF1R和CXCR2嵌段MDSC募集的结合抑制并降低了肿瘤生长，通过添加抗PD-1进一步提高。

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