Targeting the IL34-CSF1R axis improves metastatic renal cell carcinoma therapy outcome via immune-vascular crosstalk regulation
Andrea Emanuelli,
Wilfried Souleyreau,
Tiffanie Chouleur,
Bram Boeckx,
Yasmine Pobiedonoscew,
Lindsay Cooley,
Marie-Alix Derieppe,
Julie Martineau,
Damien Ambrosetti,
Jean-Christophe Bernhard,
Catherine M. Sawai,
Diether Lambrechts,
Thomas Mathivet,
Andreas Bikfalvi
Affiliations
Andrea Emanuelli
University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France
Wilfried Souleyreau
University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France
Tiffanie Chouleur
University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France
Bram Boeckx
Laboratory of Translational Genetics, Department of Human Genetics, VIB-KU Leuven, 3000 Leuven, Belgium; VIB Center for Cancer Biology, 3000 Leuven, Belgium
Yasmine Pobiedonoscew
University of Bordeaux, INSERM, U1312 BRIC, Modeling Transformation and Resistance in Leukemia Laboratory, Bordeaux, France
Lindsay Cooley
University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France
Marie-Alix Derieppe
Animalerie Mutualisée, Service Commun des Animaleries, Université de Bordeaux, 33000 Bordeaux, France
Julie Martineau
Animalerie Mutualisée, Service Commun des Animaleries, Université de Bordeaux, 33000 Bordeaux, France
Damien Ambrosetti
Department of Pathology, University Côte d'Azur, CHU Nice, Nice, France
Jean-Christophe Bernhard
Urology Department, Bordeaux University Hospital, Bordeaux, France
Catherine M. Sawai
University of Bordeaux, INSERM, U1312 BRIC, Modeling Transformation and Resistance in Leukemia Laboratory, Bordeaux, France
Diether Lambrechts
Laboratory of Translational Genetics, Department of Human Genetics, VIB-KU Leuven, 3000 Leuven, Belgium; VIB Center for Cancer Biology, 3000 Leuven, Belgium
Thomas Mathivet
University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France
Andreas Bikfalvi
University of Bordeaux, INSERM, U1312 BRIC, Tumor and Vascular Biology Laboratory, Pessac, France; Corresponding author
Summary: 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.
