Authors

Vinit Kumar, The Wistar Institute
Laxminarasimha Donthireddy, The Wistar Institute
Douglas Marvel, The Wistar Institute
Thomas Condamine, The Wistar Institute
Fang Wang, The Wistar Institute
Sergio Lavilla-Alonso, The Wistar Institute
Ayumi Hashimoto, The Wistar Institute
Prashanthi Vonteddu, The Wistar Institute
Reeti Behera, The Wistar Institute
Marlee A. Goins, Helen F. Graham Cancer Center at Christiana Care Health System
Charles Mulligan, Helen F. Graham Cancer Center at Christiana Care Health System
Brian Nam, Helen F. Graham Cancer Center at Christiana Care Health System
Neil Hockstein, Helen F. Graham Cancer Center at Christiana Care Health System
Fred Denstman, Helen F. Graham Cancer Center at Christiana Care Health System
Shanti Shakamuri, Helen F. Graham Cancer Center at Christiana Care Health System
David W. Speicher, The Wistar Institute
Ashani T. Weeraratna, The Wistar Institute
Timothy Chao, University of Pennsylvania School of Medicine
Robert H. Vonderheide, University of Pennsylvania School of Medicine
Lucia R. Languino, Thomas Jefferson UniversityFollow
Peter Ordentlich, Syndax Pharmaceuticals, Inc.
Qin Liu, The Wistar Institute
Xiaowei Xu, University of Pennsylvania School of Medicine
Albert Lo, The Wistar Institute
Ellen Puré, University of Pennsylvania School of Veterinary Medicine
Chunsheng Zhang, Merck & Co., Inc.
Andrey Loboda, Merck & Co., Inc.
Manuel A. Sepulveda, Janssen R&D
Linda A. Snyder, Janssen R&D
Dmitry I. Gabrilovich, The Wistar Institute

Document Type

Article

Presentation Date

11-13-2017

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Cell, Volume 32, Issue 5, November 2017, Pages 654-668.e5.

The published version is available at https://doi.org/10.1016/j.ccell.2017.10.005. Copyright © Elsevier

CC-BY-NC-ND

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.

Language

English

Included in

Oncology Commons

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