Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

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 demonstrate...

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Vydáno v:	Cancer cell Ročník 32; číslo 5; s. 654
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 13.11.2017
Témata:	Animals Cancer-Associated Fibroblasts - drug effects Cancer-Associated Fibroblasts - metabolism Cell Line, Tumor Granulocytes - metabolism Histone Deacetylase 2 Humans Imidazoles - pharmacology Macrophages - metabolism Mice, Inbred C57BL Monocytes - metabolism Myeloid-Derived Suppressor Cells - metabolism Neoplasms, Experimental - drug therapy Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Phenylurea Compounds - pharmacology Pyridines - pharmacology Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors Receptor, Macrophage Colony-Stimulating Factor - metabolism Receptors, Interleukin-8B - antagonists & inhibitors Receptors, Interleukin-8B - metabolism Tumor Burden - drug effects granulocytes CSF1R fibroblasts macrophages M-CSF PMN-MDSC
ISSN:	1878-3686, 1878-3686
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686 1878-3686
DOI:	10.1016/j.ccell.2017.10.005