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 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.
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.
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