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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Targeting the IL34-CSF1R axis improves metastatic renal cell carcinoma therapy outcome via immune-vascular crosstalk
Andrea Emanuelli1, Wilfried Souleyreau1, Tiffanie Chouleur1
1University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France.
Abstract:
Current therapies ultimately fail to eradicate metastatic renal cell carcinoma (RCC). Validated biomarkers and a better understanding of the mechanisms causing therapy resistance are still needed. Here we demonstrate that interleukin-34 (IL34) is associated with poor prognosis, metastasis, and therapy resistance in RCC. In mice, single-nucleus RNA sequencing and phenotyping reveal that the IL34-enriched tumor microenvironment displays immunosuppression and nonfunctional vasculature, two key features of therapy resistance. Mechanistically, IL34 increases migration of monocyte-derived tumor-associated macrophages (MD-TAMs) in primary tumors and lung metastases through colony-stimulating factor 1 receptor (CSF1R). Blockade of CSF1R by the Food and Drug Administration-approved drug pexidartinib contrasts MD-TAMs accumulation observed in the IL34-enriched microenvironment and improves response to sunitinib or anti-PD1 treatment to reduce metastatic growth. Altogether, our data highlight the role of the IL34-CSF1R axis in regulating the tumor immune-vascular crosstalk in RCC and indicate pexidartinib as a therapeutic alternative in combination with current therapies.
Insights
Interleukin-34 (IL34) drives therapy resistance in metastatic renal cell carcinoma (RCC) by promoting immunosuppression and nonfunctional vasculature. Blocking the IL34-CSF1R axis with pexidartinib may improve treatment response.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Metastatic renal cell carcinoma (RCC) remains challenging to treat, with current therapies often failing.
- Understanding mechanisms of therapy resistance and identifying predictive biomarkers are crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of interleukin-34 (IL34) in RCC progression and therapy resistance.
- To explore the therapeutic potential of targeting the IL34-CSF1R axis in metastatic RCC.
Main Methods:
- Single-nucleus RNA sequencing and phenotyping in mouse models of RCC.
- Analysis of the tumor microenvironment, including immune cell infiltration and vasculature.
- Pharmacological blockade of colony-stimulating factor 1 receptor (CSF1R) using pexidartinib.
Main Results:
- IL34 was associated with poor prognosis, metastasis, and resistance to therapy in RCC.
- IL34-enriched tumors exhibited immunosuppression and nonfunctional vasculature.
- IL34 promoted monocyte-derived tumor-associated macrophage (MD-TAM) migration via CSF1R.
- Pexidartinib treatment reduced MD-TAMs and enhanced responses to sunitinib or anti-PD1 therapy, decreasing metastatic growth.
Conclusions:
- The IL34-CSF1R axis plays a critical role in immune-vascular crosstalk within the RCC tumor microenvironment.
- Targeting IL34-CSF1R with pexidartinib represents a promising therapeutic strategy, potentially enhancing current RCC treatments.
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