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PMID: 29136508 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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

Cancer cell ·Vol. 32 ·No. 5 ·2017-00-13 ·Pages 654-668.e5

Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, Hashimoto A, Vonteddu P, Behera R, Goins MA, Mulligan C, Nam B, Hockstein N, Denstman F, Shakamuri S, Speicher DW, Weeraratna AT, Chao T, Vonderheide RH, Languino LR, Ordentlich P, Liu Q, Xu X, Lo A, Puré E, Zhang C, Loboda A, Sepulveda MA, Snyder LA, Gabrilovich DI

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.

Keywords
CSF1R M-CSF PMN-MDSC fibroblasts granulocytes macrophages
MeSH Terms
Animals Cancer-Associated Fibroblasts/drug effects,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,metabolism,pathology Phenylurea Compounds/pharmacology Pyridines/pharmacology Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors,metabolism Receptors, Interleukin-8B/antagonists & inhibitors,metabolism Tumor Burden/drug effects
Chemicals
Imidazoles JNJ-40346527 Phenylurea Compounds Pyridines Receptors, Interleukin-8B SB 225002 Receptor, Macrophage Colony-Stimulating Factor HDAC2 protein, human Histone Deacetylase 2
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Kumar Vinit
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Donthireddy Laxminarasimha
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Marvel Douglas
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Condamine Thomas
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Wang Fang
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Lavilla-Alonso Sergio
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Hashimoto Ayumi
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Vonteddu Prashanthi
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Behera Reeti
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Goins Marlee A
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Mulligan Charles
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Nam Brian
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Hockstein Neil
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Denstman Fred
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Shakamuri Shanti
Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA.
Speicher David W
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Weeraratna Ashani T
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Chao Timothy
University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Vonderheide Robert H
University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Languino Lucia R
Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Ordentlich Peter
Syndax Pharmaceuticals, Inc., Waltham, MA 02451, USA.
Liu Qin
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Xu Xiaowei
University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lo Albert
University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
Puré Ellen
University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
Zhang Chunsheng
Department of Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA 02115, USA.
Loboda Andrey
Department of Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA 02115, USA.
Sepulveda Manuel A
Janssen R&D, Spring House, PA 19477, USA.
Snyder Linda A
Janssen R&D, Spring House, PA 19477, USA.
Gabrilovich Dmitry I
Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: [email protected].
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2017.10.005
Email
[email protected]
Published
2017-00-13
Pages
654-668.e5
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC5827952
Subset
IM
Grants
NCI NIH HHS · P01 CA140043 · United States
NCI NIH HHS · P30 CA010815 · United States
NCI NIH HHS · P01 CA114046 · United States
NCI NIH HHS · R01 CA084488 · United States
NCI NIH HHS · R01 CA174746 · United States
NCI NIH HHS · P50 CA168536 · United States
Corrections
CommentIn
PMID: 29136500
External Links
PubMed source DOI: 10.1016/j.ccell.2017.10.005 PMC Full Text View journal details
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