| Literature DB >> 29136508 |
Vinit Kumar1, Laxminarasimha Donthireddy1, Douglas Marvel1, Thomas Condamine1, Fang Wang1, Sergio Lavilla-Alonso1, Ayumi Hashimoto1, Prashanthi Vonteddu1, Reeti Behera1, Marlee A Goins2, Charles Mulligan2, Brian Nam2, Neil Hockstein2, Fred Denstman2, Shanti Shakamuri2, David W Speicher3, Ashani T Weeraratna1, Timothy Chao4, Robert H Vonderheide4, Lucia R Languino5, Peter Ordentlich6, Qin Liu1, Xiaowei Xu4, Albert Lo7, Ellen Puré7, Chunsheng Zhang8, Andrey Loboda8, Manuel A Sepulveda9, Linda A Snyder9, Dmitry I Gabrilovich10.
Abstract
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.Entities:
Keywords: CSF1R; M-CSF; PMN-MDSC; fibroblasts; granulocytes; macrophages
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Year: 2017 PMID： 29136508 PMCID： PMC5827952 DOI： 10.1016/j.ccell.2017.10.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743