Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors
Open accessAbstract
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.
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Entinostat may increase MDSC infiltration in the tumor microenvironment.
“For example, entinostat may increase the infiltration of MDSC (myeloid-derived suppressor cells) in the tumor microenvironment.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Kumar et al., 2017
HDAC2 plays the main role, independent of HDAC1, in this context.
“In this context, HDAC2 plays the main role, independent of HDAC1.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Kumar et al., 2017
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- Authors
- Kumar, V., Donthireddy, L., Marvel, D., Condamine, T., Wang, F., Lavilla-Alonso, S., Hashimoto, A., Vonteddu, P., Behera, R., Goins, M. A., Mulligan, C., Nam, B., Hockstein, N., Denstman, F., Shakamuri, S., Speicher, D. W., Weeraratna, A. T., Chao, T., Vonderheide, R. H., Languino, L. R., Ordentlich, P., Liu, Q., Xu, X., Lo, A., Puré, E., Zhang, C., Loboda, A., Sepulveda, M. A., Snyder, L. A., & Gabrilovich, D. I.
- Affiliations
- The Wistar Institute (US)
- Christiana Care Health System (US)
- University of Pennsylvania (US)
- Thomas Jefferson University (US)
- Syndax Pharmaceuticals (United States) (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Janssen Research & Development (United States) (US)
- Corresponding author
- Gabrilovich, Dmitry I.
- ORCID
- Donthireddy, Laxminarasimha
- Condamine, Thomas
- Wang, Fang
- Hashimoto, Ayumi
- Behera, Reeti
- Mulligan, Charles
- Nam, Brian
- 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
- Snyder, Linda A.
- Gabrilovich, Dmitry I.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 32
- Issue
- 5
- Pages
- 654-668.e5
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5827952
- OpenAlex
- W2769869838
- Cited by
- 653
- References
- 62
- Citations by year
- 2026: 57 · 2025: 65 · 2024: 81 · 2023: 73 · 2022: 87 · 2021: 90 · 2020: 82 · 2019: 63 · 2018: 51 · 2017: 3 · 2014: 1
- FWCI
- 24.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Medicine Forum (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (RO1 CA084488, P01 CA140043, P50 CA168536, P01 CA114046)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- cancer-associated fibroblasts, polymorphonuclear myeloid-derived suppressor cells, tumor-associated macrophages, granulocyte recruitment, chemokines, HDAC2, CXCR2 antagonist, tumor microenvironment, antitumor immunity, drug resistance
- MeSH terms
- Cancer-Associated Fibroblasts, Myeloid-Derived Suppressor Cells, Animals, Granulocytes, Humans, Imidazoles, Macrophages, Mice, Inbred C57BL, Monocytes, Neoplasms, Experimental, Phenylurea Compounds, Pyridines, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Interleukin-8B, Cell Line, Tumor, Tumor Burden, Histone Deacetylase 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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