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.

中文翻译：

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癌症相关成纤维细胞通过诱导 PMN-MDSC 浸润肿瘤来中和 CSF1 受体阻断的抗肿瘤作用。

肿瘤相关巨噬细胞（TAM）对肿瘤进展的各个方面都有贡献。使用 CSF1R 抑制剂靶向 TAM 在治疗上很有吸引力，但抗肿瘤效果非常有限。在这里，我们已经确定了限制 CSF1R 靶向治疗效果的机制。我们证明癌相关成纤维细胞（CAF）是向肿瘤募集粒细胞的趋化因子的主要来源。肿瘤细胞产生的 CSF1 引起 HDAC2 介导的 CAF 中粒细胞特异性趋化因子表达的下调，从而限制了这些细胞向肿瘤的迁移。CSF1R 抑制剂治疗破坏了这种串扰，并引发肿瘤中粒细胞募集的显着增加。CSF1R抑制剂与CXCR2拮抗剂联合使用可阻断肿瘤的粒细胞浸润，显示出强大的抗肿瘤作用。