Kumar Vinit, Donthireddy Laxminarasimha, Marvel Douglas, Condamine Thomas, Wang Fang, Lavilla-Alonso Sergio, Hashimoto Ayumi, Vonteddu Prashanthi, Behera Reeti, Goins Marlee A, Mulligan Charles, Nam Brian, Hockstein Neil, Denstman Fred, Shakamuri Shanti, Speicher David W, Weeraratna Ashani T, Chao Timothy, Vonderheide Robert H, Languino Lucia R, Ordentlich Peter, Liu Qin, Xu Xiaowei, Lo Albert, Puré Ellen, Zhang Chunsheng, Loboda Andrey, Sepulveda Manuel A, Snyder Linda A, Gabrilovich Dmitry I
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Cancer Cell. 2017 Nov 13;32(5):654-668.e5. doi: 10.1016/j.ccell.2017.10.005.
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.
肿瘤相关巨噬细胞（TAM）在肿瘤进展的各个方面都发挥着作用。使用集落刺激因子1受体（CSF1R）抑制剂靶向TAM具有治疗吸引力，但抗肿瘤效果非常有限。在此，我们确定了限制CSF1R靶向治疗效果的机制。我们证明，癌相关成纤维细胞（CAF）是将粒细胞募集到肿瘤中的趋化因子的主要来源。肿瘤细胞产生的CSF1导致CAF中HDAC2介导的粒细胞特异性趋化因子表达下调，这限制了这些细胞向肿瘤的迁移。用CSF1R抑制剂治疗会破坏这种相互作用，并引发粒细胞向肿瘤募集的显著增加。将CSF1R抑制剂与CXCR2拮抗剂联合使用可阻断粒细胞对肿瘤的浸润，并显示出强大的抗肿瘤作用。
