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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Bibliographic Details
Published in:Cancer cell Vol. 32; no. 5; p. 654
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 13.11.2017
Subjects:
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
Online Access:Get more information
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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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2017.10.005