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Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.
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- article
- Animals
- Cancer-Associated Fibroblasts
- Cell Line
- Tumor
- Granulocytes
- Histone Deacetylase 2
- Humans
- Imidazoles
- Macrophages
- Mice
- Inbred C57BL
- Monocytes
- Myeloid-Derived Suppressor Cells
- Neoplasms
- Experimental
- Phenylurea Compounds
- Pyridines
- Receptor
- Macrophage Colony-Stimulating Factor
- Receptors
- Interleukin-8B
- Tumor Burden
- Cell Line, Tumor
- Mice, Inbred C57BL
- Neoplasms, Experimental
- Receptor, Macrophage Colony-Stimulating Factor
- Receptors, Interleukin-8B
- Medicine and Health Sciences
- Oncology