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

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.

Recommended Citation

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.; and Gabrilovich, Dmitry I., "Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors." (2017). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 61.
https://jdc.jefferson.edu/kimmelgrandrounds/61

Language

English